|
1
|
Zuo S, Yang W, Zhang S, Sun S, Lu S, Lu C, Li W. Telitacicept: A New Therapy for the Treatment of Optic Neuromyelitis Spectrum Disease Associated with Other Autoimmune Disorders. Biologics 2025; 19:149-155. [PMID: 40196354 PMCID: PMC11974576 DOI: 10.2147/btt.s508605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 03/26/2025] [Indexed: 04/09/2025]
Abstract
Neuromyelitis optica spectrum disorders (NMOSD) are primarily autoimmune diseases mediated by B cells and AQP4-IgG antibodies, typically affecting the optic nerves and spinal cord, and are characterised by high relapse rates and significant disability. We present two cases of NMOSD patients who also had systemic lupus erythematosus (SLE), with one case additionally complicated by myasthenia gravis (MG). Both patients initially received first-line treatment with corticosteroids; however, no clinical improvement was observed; As a result, the treatment was switched to the dual-target biologic agent, Telitacicept. Following the administration of Telitacicept, both patients demonstrated significant improvements in clinical symptoms, daily functional abilities, and imaging findings. This report highlights the successful use of Telitacicept in treating NMOSD complicated by other autoimmune diseases, which may serve as an important reference for the management of NMOSD.
Collapse
Affiliation(s)
- Shaomin Zuo
- Department of Neurology, People’s Hospital of Henan University, Zhengzhou, People’s Republic of China
- Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou, People’s Republic of China
| | - Wenning Yang
- Department of Neurology, People’s Hospital of Henan University, Zhengzhou, People’s Republic of China
- Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou, People’s Republic of China
| | - Siyu Zhang
- Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou, People’s Republic of China
- Department of Neurology, People’s Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Shuyue Sun
- Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou, People’s Republic of China
- Department of Neurology, People’s Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Songke Lu
- Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou, People’s Republic of China
- Department of Neurology, People’s Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Chengcheng Lu
- Department of Neurology, People’s Hospital of Henan University, Zhengzhou, People’s Republic of China
- Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou, People’s Republic of China
| | - Wei Li
- Department of Neurology, People’s Hospital of Henan University, Zhengzhou, People’s Republic of China
| |
Collapse
|
|
2
|
Coffey DG, Ataca Atilla P, Atilla E, Landgren O, Cowan AJ, Simon S, Pont MJ, Comstock ML, Hill GR, Riddell SR, Green DJ. Single-cell analysis of the multiple myeloma microenvironment after γ-secretase inhibition and CAR T-cell therapy. Blood 2025; 145:220-233. [PMID: 39374522 PMCID: PMC11738034 DOI: 10.1182/blood.2024025231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 09/23/2024] [Accepted: 09/23/2024] [Indexed: 10/09/2024] Open
Abstract
ABSTRACT Chimeric antigen receptor (CAR) T cells and bispecific antibodies targeting B-cell maturation antigen (BCMA) have significantly advanced the treatment of relapsed and refractory multiple myeloma. Resistance to BCMA-targeting therapies, nonetheless, remains a significant challenge. BCMA shedding by γ-secretase is a known resistance mechanism, and preclinical studies suggest that inhibition may improve anti-BCMA therapy. Leveraging a phase 1 clinical trial of the γ-secretase inhibitor (GSI), crenigacestat, with anti-BCMA CAR T cells (FCARH143), we used single-nuclei RNA sequencing and assay for transposase-accessible chromatin sequencing to characterize the effects of GSI on the tumor microenvironment. The most significant impacts of GSI involved effects on monocytes, which are known to promote tumor growth. In addition to observing a reduction in the frequency of nonclassical monocytes, we also detected significant changes in gene expression, chromatin accessibility, and inferred cell-cell interactions after exposure to GSI. Although many genes with altered expression are associated with γ-secretase-dependent signaling, such as Notch, other pathways were affected, indicating GSI has far-reaching effects. Finally, we detected monoallelic deletion of the BCMA locus in some patients with prior exposure to anti-BCMA therapy, which significantly correlated with reduced progression-free survival (PFS; median PFS, 57 vs 861 days). GSIs are being explored in combination with the full spectrum of BCMA-targeting agents, and our results reveal widespread effects of GSI on both tumor and immune cell populations, providing insight into mechanisms for enhancing BCMA-directed therapies.
Collapse
Affiliation(s)
- David G. Coffey
- Myeloma Division, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
| | | | - Erden Atilla
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA
| | - Ola Landgren
- Myeloma Division, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
| | - Andrew J. Cowan
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA
| | - Sylvain Simon
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Margot J. Pont
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
- Galapagos B.V., Oegstgeest, The Netherlands
| | - Melissa L. Comstock
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Geoffrey R. Hill
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Stanley R. Riddell
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Damian J. Green
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
- Division of Transplantation and Cellular Therapy, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
| |
Collapse
|
|
3
|
Su Y, Liu S, Long C, Zhou Z, Zhou Y, Tang J. The cross-talk between B cells and macrophages. Int Immunopharmacol 2024; 143:113463. [PMID: 39467344 DOI: 10.1016/j.intimp.2024.113463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 10/18/2024] [Accepted: 10/18/2024] [Indexed: 10/30/2024]
Abstract
B cells and macrophages are significant immune cells that maintain the immune balance of the body. B cells are involved in humoral immunity, producing immune effects mainly by secreting antibodies. Macrophages participate in non-specific and specific immune responses. To gain a further understanding of macrophages and B cells, researchers have not only paid attention to the unidirectional influence between B cells and macrophages, but also have focused on the cross-talk between them, and the effect of this cross talk on diseases. Therefore, this review summarizes the influence of macrophages on B cells, the ways and mechanisms by which B cells affect macrophages, and their cross-talk, leading to a more comprehensive understanding of the mechanism of the interaction between macrophages and B cells.
Collapse
Affiliation(s)
- Yahui Su
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Cancer Research Institute, Basic School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Siyi Liu
- Cancer Research Institute, Basic School of Medicine, Central South University, Changsha, Hunan 410078, China
| | - Chen Long
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Zihua Zhou
- Department of Oncology, Loudi Central Hospital, Loudi 417000, China
| | - Yanhong Zhou
- Cancer Research Institute, Basic School of Medicine, Central South University, Changsha, Hunan 410078, China.
| | - Jingqiong Tang
- Department of Geriatrics, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
| |
Collapse
|
|
4
|
Stohl W, Wu Y, Stohl M. Contributions of each of the BAFF receptors to the lymphocyte profiles in C57BL/6 mice. Immunology 2024; 173:689-711. [PMID: 39215598 DOI: 10.1111/imm.13856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 08/18/2024] [Indexed: 09/04/2024] Open
Abstract
BAFF, a vital B cell survival and differentiation factor, has three receptors: B-cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) and BR3. Although B cells are greatly reduced in B6.Baff-/- (which harbour no BAFF) and B6.Br3-/- mice (which harbour supra-normal levels of BAFF), the distributions of B cell subsets and relationships between Foxp3+ and CD4+ cells in these mice differ. Using a large panel of B6 congenic knockout and/or transgenic mice, we demonstrate that (1) supra-normal levels of BAFF per se do not explain the phenotypic differences between B6.Baff-/- and B6.Br3-/- mice; (2) B cells are expanded in B6.Taci-/- mice, with preferential expansion of follicular (FO) B cells at the expense of CD19+CD21-/loCD23-/lo B cells but without the preferential expansion of Foxp3+ cells observed in B6 mice bearing a Baff transgene; (3) despite no expansion in total B cells, percentages of FO B cells and marginal zone B cells are higher and percentages of CD19+CD21-/loCD23-/lo B cells are lower in young B6.Bcma-/- mice, consistent with the inability of B6.Br3-/-.Taci-/- mice to recapitulate the B cell profile of B6.Baff-/- mice; and (4) percentages of Foxp3+ cells in B6.Br3-/-.Taci-/- mice are intermediate between those in B6.Br3-/- and B6.Taci-/- mice despite the B cell profile of B6.Br3-/-.Taci-/- mice strongly resembling that of B6.Br3-/- mice. Collectively, our findings point to a non-redundant role for each of the BAFF receptors in determining the ultimate lymphocyte profile of the host. This may have clinically relevant ramifications in that the degree that a candidate therapeutic agent blocks engagement of any given individual BAFF receptor may affect its clinical utility.
Collapse
Affiliation(s)
- William Stohl
- Division of Rheumatology, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - Ying Wu
- Division of Rheumatology, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - Malka Stohl
- New York State Psychiatric Institute, New York, New York, USA
| |
Collapse
|
|
5
|
Chen Y, Chen M, Liu Y, Li Q, Xue Y, Liu L, Liang R, Xiong Y, Zhao J, Chen J, Lin W, Wang J, Pan YF, Stohl W, Zheng SG. BAFF promotes follicular helper T cell development and germinal center formation through BR3 signal. JCI Insight 2024; 9:e183400. [PMID: 39325665 PMCID: PMC11601555 DOI: 10.1172/jci.insight.183400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 09/18/2024] [Indexed: 09/28/2024] Open
Abstract
T follicular helper (Tfh) cells represent an important subset of CD4+ T cells that is crucial to the maturation and differentiation of B cells and the production of high-affinity antibodies. Because B cell activating-factor (BAFF), a vital B cell survival factor, is also crucial to B cell maturation and differentiation, we assessed the effects of BAFF on Tfh cell development and function. We demonstrated that deficiency of BAFF, but not of APRIL, markedly inhibited Tfh cell development, germinal center (GC) formation, and antigen-specific antibody production. The promoting effect of BAFF on Tfh cell development was dependent on expression of BR3 on T cells, and its promoting effect on GC formation was dependent on expression of BR3 on both T cells and B cells. BAFF directly promoted expression of the Tfh cell-characteristic genes via NF-κB signaling. This effect did need BR3 expression. Thus, BAFF not only has direct effects on B cells, but it also has direct effects on Tfh cell differentiation via engagement of BR3, which collectively promoted GC formation and production of high-affinity antibodies. This dual effect of BAFF on B cells and Tfh cells may help explain the clinical utility of BAFF antagonists in the management of certain autoimmune diseases.
Collapse
Affiliation(s)
- Ye Chen
- Department of Rheumatology & Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Division of Rheumatology, Department of Internal Medicine, and
| | - Maogen Chen
- Organ Transplant Center, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yu Liu
- Clinical Research Center, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, China
| | - Qiang Li
- Organ Transplant Center, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Youqiu Xue
- Department of Rheumatology & Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liu Liu
- Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Rongzhen Liang
- Department of Rheumatology & Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiding Xiong
- Department of Rheumatology & Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Zhao
- Department of Rheumatology & Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingrong Chen
- Department of Rheumatology & Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weidong Lin
- Department of Rheumatology & Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Julie Wang
- Department of Rheumatology & Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yun Feng Pan
- Division of Rheumatology, Department of Internal Medicine, and
| | - William Stohl
- Division of Rheumatology, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - Song Guo Zheng
- Department of Rheumatology & Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
6
|
Stohl W, Wu Y, Stohl M. T cell Dissimilarities in B Cell Activating Factor-Deficient Versus B Cell Activating Factor Receptor 3-Deficient Systemic Lupus Erythematosus-Prone NZM 2328 Mice as Contributors to Their Divergent Clinical Outcomes. ACR Open Rheumatol 2024; 6:756-768. [PMID: 39143363 PMCID: PMC11557988 DOI: 10.1002/acr2.11712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 05/29/2024] [Accepted: 06/08/2024] [Indexed: 08/16/2024] Open
Abstract
OBJECTIVE We assessed the contributions of B cell and T cell subsets to the disparate clinical outcomes in NZM.Baff-/- and NZM.Br3-/- mice. METHODS We assessed in NZM wild-type, NZM.Baff-/-, and NZM.Br3-/- mice numbers and percentages of B cells and subsets, T cells and subsets, and in vivo proliferation and survival of forkhead box P3 (Foxp3)+ cells by fluorescence-activated cell sorting. Relationships between percentages of Foxp3+ cells and numbers of CD19+ and CD4+ cells were assessed by linear regressions. RESULTS In each age and sex cohort, percentages and numbers of CD19+ cells were similar in NZM.Baff-/- and NZM.Br3-/- mice. Percentages of CD3+ and CD4+ cells were greater in NZM.Br3-/- than in NZM.Baff-/- mice, with the CD4 to CD3 cell ratios being greater in NZM.Br3-/- than in NZM.Baff-/- mice and percentages of Foxp3+ cells in NZM.Br3-/- mice being lower than in NZM.Baff-/- mice. Percentages of Foxp3+ cells correlated positively with CD19+ cells in NZM.Baff-/- mice but negatively in NZM.Br3-/- mice. In vivo proliferation and survival of Foxp3+ cells were lower in NZM.Baff-/- mice than in NZM.Br3-/- mice. CONCLUSION Differences between NZM.Baff-/- and NZM.Br3-/- mice in Foxp3+ cells and their relationships with CD19+ cells may have more to do with their divergent clinical outcomes than do differences in numbers of B cells. These unexpected findings suggest that B cell activating factor (BAFF)-B cell maturation antigen (BCMA) or BAFF-Transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) interactions may help drive development of clinical systemic lupus erythematosus (SLE) even under conditions of considerable B cell depletion. Insufficient blocking of BAFF-BCMA and BAFF-TACI interactions may lie at the heart of incomplete clinical response to BAFF-targeting agents in human SLE.
Collapse
Affiliation(s)
- William Stohl
- University of Southern California Keck School of MedicineLos Angeles
| | - Ying Wu
- University of Southern California Keck School of MedicineLos Angeles
| | - Malka Stohl
- New York State Psychiatric InstituteNew York City
| |
Collapse
|
|
7
|
Balasubramaniam M, Mokhtar AMA. Past and present discovery of the BAFF/APRIL system - A bibliometric study from 1999 to 2023. Cell Signal 2024; 120:111201. [PMID: 38714287 DOI: 10.1016/j.cellsig.2024.111201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 04/30/2024] [Accepted: 05/01/2024] [Indexed: 05/09/2024]
Abstract
Cytokines from the Tumour Necrosis Factor (TNF) family are important regulators of both physiological and pathological processes. The discovery of novel TNF ligands and receptors, BAFF and APRIL, have opened up new possibilities for scientists to explore the effect of these cytokines on the human immune system. The role of BAFF/APRIL system in B lymphocytes is particularly important for survival and maintenance of homeostasis. Aberrant expression of the system is associated with various immunological disorders. Hence, this study provides a comprehensive overview of the past and present BAFF/APRIL system research development in a bibliometric perspective. To our best knowledge, this is the first ever bibliometric analysis conducted focusing on the BAFF/APRIL system. A total of 1055 relevant documents were retrieved from WoSCC. Microsoft Excel, VOSviewer, and Biblioshiny of R studio were bibliometric tools used to analyse the scientific literature. From 1999, the annual publications showed an upward trend, with Journal of Immunology being the most productive journal. USA leads the race for BAFF/APRIL system research developments. Pascal Schneider, a senior researcher affiliated with University of Lausanne, Switzerland was recognised as the most productive author and institution in the BAFF/APRIL system research field. The research focus transitioned from focusing on the role of the system in B cell biology, to immunological disorders and finally to development of BAFF/APRIL targeting drugs. Despite several studies elucidating briefly the pathway mechanism of BAFF/APRIL system in B-cell selection, substantial research on the mechanism of action in disease models and T cell activation and development of immunomodulating drugs from natural origins remains largely unexplored. Therefore, future research focusing on these areas are crucial for the deeper understanding of the system in disease manifestations and progression allowing a better treatment management for various immunological disorders.
Collapse
Affiliation(s)
- Muggunna Balasubramaniam
- Small G protein Research Group, Bioprocess Technology Division, School of Industrial Technology, Universiti Sains Malaysia, 11800 Gelugor, Penang, Malaysia; Green Biopolymer Coating and Packaging Centre, School of Industrial Technology, Universiti Sains Malaysia, 11800 Gelugor, Penang, Malaysia
| | - Ana Masara Ahmad Mokhtar
- Small G protein Research Group, Bioprocess Technology Division, School of Industrial Technology, Universiti Sains Malaysia, 11800 Gelugor, Penang, Malaysia; Green Biopolymer Coating and Packaging Centre, School of Industrial Technology, Universiti Sains Malaysia, 11800 Gelugor, Penang, Malaysia.
| |
Collapse
|
|
8
|
Nakashima T, Kagoya Y. Current progress of CAR-T-cell therapy for patients with multiple myeloma. Int J Hematol 2024; 120:15-22. [PMID: 38777913 DOI: 10.1007/s12185-024-03794-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 05/11/2024] [Accepted: 05/16/2024] [Indexed: 05/25/2024]
Abstract
Currently available chimeric antigen receptor (CAR)-engineered T-cell therapies targeting B-cell maturation antigen (BCMA), namely, idecabtagene vicleucel and ciltacabtagene autoleucel, have shown marked efficacy against relapsed and refractory multiple myeloma. However, further improvement in CAR-T-cell function is warranted as most patients treated with these products eventually relapse due to various mechanisms such as antigen loss and T-cell dysfunction or disappearance. Strategies for improving CAR-T-cell function include targeting of dual antigens, enhancing cell longevity through genetic modification, and eliminating the immunosuppressive tumor microenvironment. Serious side effects can also occur after CAR-T-cell infusions. Although understanding of the molecular pathogenesis of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome is growing, the unique movement disorder caused by BCMA-targeted therapy is less understood, and its molecular mechanisms must be further elucidated to establish better management strategies. In this article, we will review the current status of BCMA-targeting CAR-T-cell therapy. We will also highlight progress in the development of CAR-T cells targeting other antigens, as well as universal allogeneic CAR-T cells and bispecific antibodies.
Collapse
Affiliation(s)
- Takahiro Nakashima
- Division of Tumor Immunology, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
- Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yuki Kagoya
- Division of Tumor Immunology, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| |
Collapse
|
|
9
|
Carvalho-Santos A, Ballard Kuhnert LR, Hahne M, Vasconcellos R, Carvalho-Pinto CE, Villa-Verde DMS. Anti-inflammatory role of APRIL by modulating regulatory B cells in antigen-induced arthritis. PLoS One 2024; 19:e0292028. [PMID: 38691538 PMCID: PMC11062543 DOI: 10.1371/journal.pone.0292028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 04/02/2024] [Indexed: 05/03/2024] Open
Abstract
APRIL (A Proliferation-Inducing Ligand), a member of the TNF superfamily, was initially described for its ability to promote proliferation of tumor cells in vitro. Moreover, this cytokine has been related to the pathogenesis of different chronic inflammatory diseases, such as rheumatoid arthritis. This study aimed to evaluate the ability of APRIL in regulating B cell-mediated immune response in the antigen-induced arthritis (AIA) model in mice. AIA was induced in previously immunized APRIL-transgenic (Tg) mice and their littermates by administration of antigen (mBSA) into the knee joints. Different inflammatory cell populations in spleen and draining lymph nodes were analyzed using flow cytometry and the assay was performed in the acute and chronic phases of the disease, while cytokine levels were assessed by ELISA. In the acute AIA, APRIL-Tg mice developed a less severe condition and a smaller inflammatory infiltrate in articular tissues when compared with their littermates. We also observed that the total cellularity of draining lymph nodes was decreased in APRIL-Tg mice. Flow cytometry analysis revealed an increase of CD19+IgM+CD5+ cell population in draining lymph nodes and an increase of CD19+CD21hiCD23hi (B regulatory) cells in APRIL-Tg mice with arthritis as well as an increase of IL-10 and CXCL13 production in vitro.
Collapse
Affiliation(s)
- Adriana Carvalho-Santos
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
- Experimental Pathology Laboratory, Department of Immunobiology, Biology Institute, Fluminense Federal University, Niterói, RJ, Brazil
| | - Lia Rafaella Ballard Kuhnert
- Experimental Pathology Laboratory, Department of Immunobiology, Biology Institute, Fluminense Federal University, Niterói, RJ, Brazil
| | - Michael Hahne
- Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, CNRS, Label "Equipe FRM", Montpellier, France
| | - Rita Vasconcellos
- Experimental Pathology Laboratory, Department of Immunobiology, Biology Institute, Fluminense Federal University, Niterói, RJ, Brazil
| | - Carla Eponina Carvalho-Pinto
- Experimental Pathology Laboratory, Department of Immunobiology, Biology Institute, Fluminense Federal University, Niterói, RJ, Brazil
| | - Déa Maria Serra Villa-Verde
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
- National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
- Rio de Janeiro Research Network on Neuroinflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
- INOVA-IOC Network on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
| |
Collapse
|
|
10
|
Huang HW, Chen CC, Lin KI, Hsu TL, Wong CH. Single Site N-Glycosylation of B Cell Maturation Antigen (BCMA) Inhibits γ-Secretase-Mediated Shedding and Improves Surface Retention and Cell Survival. ACS Chem Biol 2024; 19:153-161. [PMID: 38085681 DOI: 10.1021/acschembio.3c00592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2024]
Abstract
B cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor (TNFR) family, on the cell surface plays a key role in maintaining the survival of plasma cells and malignant as well as inflammatory accessory cells. Therefore, targeting BCMA or disrupting its interaction with ligands has been a potential approach to cancer therapy. BCMA contains a single N-glycosylation site, but the function of N-glycan on BCMA is not understood. Here, we found that the N-glycosylation of BCMA promoted its cell-surface retention while removing the N-glycan increased BCMA secretion through γ-secretase-mediated shedding. Addition of γ-secretase inhibitor prevented nonglycosylated BCMA from shedding and protected cells from dexamethasone and TRAIL-induced apoptosis.
Collapse
Affiliation(s)
- Han-Wen Huang
- Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan
| | - Chen-Chun Chen
- Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan
| | - Kuo-I Lin
- Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan
| | - Tsui-Ling Hsu
- Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan
| | - Chi-Huey Wong
- Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan
- Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States
| |
Collapse
|
|
11
|
Biltibo E, Berdeja JG. SOHO State-of-the-Art Updates and Next Questions | BCMA-Directed CAR T-Cells: Early Results and Future Directions. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2023; 23:310-321. [PMID: 36925390 PMCID: PMC10121830 DOI: 10.1016/j.clml.2023.01.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023]
Abstract
Despite continued advances that have led to improved survival of patients with multiple myeloma (MM) over the years, MM remains largely incurable with overall survival in patients who have progressed after proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody therapy measured in months. Better understanding of the immunopathology of MM has led to the discovery of newer treatment targets like B-cell maturation antigen (BCMA). BCMA is a tumor necrosis factor receptor superfamily expressed on normal B-lymphocytes and malignant plasma cells with a vital role in proliferation, maturation, and differentiation of normal and malignant plasma cells. Antibody drug conjugates, chimeric antigen receptor (CAR) T-cells and bispecific T-cell engagers targeting the BCMA antigen are now available within and outside of clinical trials for treatment of triple class refractory MM. This review article focuses on the evolution, safety, efficacy, and limitations of BCMA-directed CAR T-cell therapies. It also discusses the challenges unveiled by the incorporation of these CAR T-cells in the treatment paradigm of MM and deliberates on the future of CAR T-cell therapy within MM.
Collapse
Affiliation(s)
- Eden Biltibo
- Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN.
| | | |
Collapse
|
|
12
|
Swan D, Murphy P, Glavey S, Quinn J. Bispecific Antibodies in Multiple Myeloma: Opportunities to Enhance Efficacy and Improve Safety. Cancers (Basel) 2023; 15:cancers15061819. [PMID: 36980705 PMCID: PMC10046900 DOI: 10.3390/cancers15061819] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/13/2023] [Accepted: 03/15/2023] [Indexed: 03/19/2023] Open
Abstract
Multiple myeloma (MM) is the second most common haematological neoplasm of adults in the Western world. Overall survival has doubled since the advent of proteosome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies. However, patients with adverse cytogenetics or high-risk disease as determined by the Revised International Staging System (R-ISS) continue to have poorer outcomes, and triple-refractory patients have a median survival of less than 1 year. Bispecific antibodies (BsAbs) commonly bind to a tumour epitope along with CD3 on T-cells, leading to T-cell activation and tumour cell killing. These treatments show great promise in MM patients, with the first agent, teclistamab, receiving regulatory approval in 2022. Their potential utility is hampered by the immunosuppressive tumour microenvironment (TME), a hallmark of MM, which may limit efficacy, and by undesirable adverse events, including cytokine release syndrome (CRS) and infections, some of which may be fatal. In this review, we first consider the means of enhancing the efficacy of BsAbs in MM. These include combining BsAbs with other drugs that ameliorate the effect of the immunosuppressive TME, improving target availability, the use of BsAbs directed against multiple target antigens, and the optimal time in the treatment pathway to employ BsAbs. We then discuss methods to improve safety, focusing on reducing infection rates associated with treatment-induced hypogammaglobulinaemia, and decreasing the frequency and severity of CRS. BsAbs offer a highly-active therapeutic option in MM. Improving the efficacy and safety profiles of these agents may enable more patients to benefit from these novel therapies and improve outcomes for patients with high-risk disease.
Collapse
Affiliation(s)
- Dawn Swan
- Correspondence: ; Tel.: +353-1-809-3000
| | | | | | | |
Collapse
|
|
13
|
Stohl HE, Stohl W. Maternal and cord blood BAFF and APRIL levels during pregnancy. Am J Reprod Immunol 2023; 89:e13654. [PMID: 36398594 DOI: 10.1111/aji.13654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 10/21/2022] [Accepted: 11/08/2022] [Indexed: 11/19/2022] Open
Abstract
PROBLEM Dysregulation of factors vital to the survival B cells and/or plasma cells, such as BAFF and APRIL, could be detrimental to a pregnancy. METHOD OF STUDY Serially collected first-, second-, and third-trimester serum samples were measured for BAFF and APRIL by ELISA from 150 pregnant women (71 healthy + 79 with a chronic medical disease) at a single medical center. Postpartum serum samples were also collected from the majority of these women. Matched third-trimester and cord blood samples were collected from 168 women (86 healthy + 82 with a chronic medical disease). Data were analyzed by chi-square statistic, unpaired t-test, paired t-test, Mann-Whitney rank sum test, Wilcoxon signed rank test, Spearman rank order correlation, and receiver operator characteristic (ROC) curve analyses as appropriate. RESULTS Maternal serum BAFF levels declined as the pregnancies progressed and rebounded postpartum, whereas serum APRIL levels remained relatively flat throughout pregnancy and postpartum. Cord BAFF and APRIL levels correlated positively with gestation age and were considerably greater than the corresponding maternal third-trimester serum BAFF and APRIL levels, respectively. In women who developed preeclampsia, third-trimester BAFF levels were greater, rather than lower, than their corresponding second-trimester BAFF levels. ROC curve analysis suggested a potential role for third-trimester serum BAFF level as a biomarker of preeclampsia. CONCLUSIONS BAFF and APRIL are differentially regulated in the mother during and following pregnancy, whereas each is upregulated in the developing fetus. An increase in third-trimester serum BAFF level may portend development of preeclampsia.
Collapse
Affiliation(s)
- Hindi E Stohl
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Los Angeles, California, USA
| | - William Stohl
- Division of Rheumatology, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA
| |
Collapse
|
|
14
|
Alomari M, Kunacheewa C, Manasanch EE. The role of soluble B cell maturation antigen as a biomarker in multiple myeloma. Leuk Lymphoma 2023; 64:261-272. [PMID: 36282671 DOI: 10.1080/10428194.2022.2133540] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Currently used stratification models in myeloma precursor disease as well as staging systems and response criteria in myeloma have limitations including failure to identify functionally high-risk myeloma patients. B-cell maturation antigen, a transmembrane glycoprotein required for long-lived plasma cells, is specific and expressed by myeloma cells. When it sheds from the surface of myeloma cells it can be measured in the blood as serum (sBCMA) and correlated with clinical outcomes in myeloma precursor disease as well as in active myeloma. We performed a literature review using PubMed and found 825 articles since 1992 of which any articles related to sBCMA were reviewed. These studies show the potential of sBCMA to become an important biomarker in myeloma. Here, we describe the potential advantages of sBCMA in the biology, diagnosis, prognosis, and surveillance of myeloma, while also reviewing the challenges that lie ahead before it can be implemented as a clinical tool.
Collapse
Affiliation(s)
- Mohammed Alomari
- Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chutima Kunacheewa
- Division of Hematology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Elisabet E Manasanch
- Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| |
Collapse
|
|
15
|
Kumar G, Axtell RC. Dual Role of B Cells in Multiple Sclerosis. Int J Mol Sci 2023; 24:2336. [PMID: 36768658 PMCID: PMC9916779 DOI: 10.3390/ijms24032336] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/12/2023] [Accepted: 01/21/2023] [Indexed: 01/26/2023] Open
Abstract
B cells have emerged as an important immune cell type that can be targeted for therapy in multiple sclerosis (MS). Depleting B cells with anti-CD20 antibodies is effective in treating MS. Yet, atacicept treatment, which blocks B-cell Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL), two cytokines important for B cell development and function, paradoxically increases disease activity in MS patients. The reason behind the failure of atacicept is not well understood. The stark differences in clinical outcomes with these therapies demonstrate that B cells have both inflammatory and anti-inflammatory functions in MS. In this review, we summarize the importance of B cells in MS and discuss the different B cell subsets that perform inflammatory and anti-inflammatory functions and how therapies modulate B cell functions in MS patients. Additionally, we discuss the potential anti-inflammatory functions of BAFF and APRIL on MS disease.
Collapse
Affiliation(s)
| | - Robert C. Axtell
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
| |
Collapse
|
|
16
|
Zhang M, Gray F, Cushman I, Wurmser A, Chan H, Couto S, Wang M, Nakayama Y, Hagner P, Al-Masri H, Williams S, Hersey S. A Novel BCMA Immunohistochemistry Assay Reveals a Heterogenous and Dynamic BCMA Expression Profile in Multiple Myeloma. Mod Pathol 2023; 36:100050. [PMID: 36788077 DOI: 10.1016/j.modpat.2022.100050] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/22/2022] [Accepted: 11/08/2022] [Indexed: 01/13/2023]
Abstract
B-cell maturation antigen (BCMA) is a promising target for the treatment of multiple myeloma (MM) because the expression of this protein is largely limited to B-cell sets, plasma cells, MM, and other B-cell malignancies. Early studies assessing BCMA protein expression and localization have used insufficiently qualified immunohistochemistry assays, which have reported broad ranges of BCMA expression. As a result, our understanding of BCMA tissue expression derived from these data is limited, specifically the prevalence of BCMA expression on the cell surface/membrane, which has mechanistic relevance to the antimyeloma activity of several novel biotherapeutics. Here, we report on the qualification and application of a novel anti-BCMA immunohistochemistry antibody, 805G12. This antibody shows robust detection of BCMA in formalin-fixed, decalcified bone marrow tissue and provides key insights into membrane BCMA expression. The clone 805G12, which was raised against an intracellular C-terminal domain peptide of membrane BCMA, exhibited increased sensitivity and superior specificity across healthy and diseased tissue compared with the frequently referenced commercial reagent AF193. The new clone also demonstrated a broad range of expression of BCMA in MM and diffuse large B-cell lymphoma specimens. Additionally, cross-reactivity with closely related tumor necrosis factor receptor family members was observed with AF193 but not with 805G12. Furthermore, via established 805G12 and other independent BCMA assays, it was concluded that proteolytic processing by γ-secretase contributes to the levels of BCMA localized to the plasma membrane. As BCMA-directed therapeutics emerge to address the need for more effective treatment in the relapsed or refractory MM disease setting, the implementation of a qualified assay would ensure that reliable and consistent data on BCMA surface expression are used to inform clinical trial decisions and patient responses.
Collapse
Affiliation(s)
| | - Falon Gray
- Bristol Myers Squibb, Princeton, New Jersey.
| | | | | | - Henry Chan
- Bristol Myers Squibb, Princeton, New Jersey
| | - Suzana Couto
- Formerly Celgene Corporation, a Bristol Myers Squibb Company, Princeton, New Jersey
| | - Maria Wang
- Bristol Myers Squibb, Princeton, New Jersey
| | | | | | | | | | | |
Collapse
|
|
17
|
Xie J, Fan X, Su Y, Zhou H, Cao S, Zhu X, Zhu M, He C, Wang Y, Fan L, Ge Q, Zhu J, Liu B, Chen X, Xie Y, Ma L, Liu Y, Chen J, Wang H, Li Z. Pharmacokinetic Characteristics, Safety, and Tolerability of Telitacicept, an Injectable Recombinant Human B-Lymphocyte Stimulating Factor Receptor-Antibody Fusion Protein, in Healthy Chinese Subjects. Clin Pharmacol Drug Dev 2022; 11:1273-1283. [PMID: 35844038 PMCID: PMC9796261 DOI: 10.1002/cpdd.1136] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 06/06/2022] [Indexed: 01/27/2023]
Abstract
Telitacicept, an injectable recombinant human B-lymphocyte stimulating factor receptor-antibody fusion protein, is a new dual B lymphocyte stimulator (BLyS)/APRIL (a proliferation-inducing ligand) inhibitor that effectively blocks proliferation of B lymphocytes. This study evaluates the pharmacokinetic characteristics, tolerability, and safety of a single subcutaneous injection of various doses (80, 160, and 240 mg) of telitacicept in healthy Chinese subjects. This trial is a single-center, randomized, open-label phase I clinical study that includes three dose groups (80, 160, and 240 mg) with 12 subjects in each dose group. The subjects were randomly assigned to different dose groups in a 1:1:1 ratio for a single subcutaneous administration trial. After a single dose, the maximum serum concentration (Cmax ) of total and free telitacicept was reached within 0.5-1 days. The elimination half-lives of total and free telitacicept at doses of 80-240 mg were 10.9-11.9 days and 11-12.5 days, respectively. The formation and elimination of the BLyS-telitacicept complex were much slower; the median time to Cmax was 15-57 days and was significantly prolonged with increasing dose. Only two of the 36 healthy subjects had positive antidrug antibodies with antibody titers of 1:15. The severity of adverse events was mild or moderate, and no higher treatment-emergent adverse events were reported. In conclusion, total telitacicept within a dose range of 80-240 mg and free telitacicept within a dose range of 160-240 mg had linear pharmacokinetic characteristics.
Collapse
Affiliation(s)
- Jing Xie
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina
| | - Xiaoyun Fan
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina,The First Affiliated Hospital of Jinan UniversityGuangzhouGuangdongChina
| | - Yue Su
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina,School of Public FoundationBengbu Medical CollegeBengbuAnhuiChina
| | - Huan Zhou
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina,School of Public FoundationBengbu Medical CollegeBengbuAnhuiChina,School of PharmacyBengbu Medical CollegeBengbuAnhuiChina
| | - Shugang Cao
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina,The Affiliated Hefei Hospital of Anhui Medical UniversityHefeiAnhuiChina
| | - Xingyu Zhu
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina,School of PharmacyBengbu Medical CollegeBengbuAnhuiChina
| | - Minhui Zhu
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina,School of PharmacyBengbu Medical CollegeBengbuAnhuiChina
| | - Cuixia He
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina,School of PharmacyBengbu Medical CollegeBengbuAnhuiChina
| | - Ying Wang
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina
| | - Ling Fan
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina
| | - Qin Ge
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina
| | - Juan Zhu
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina
| | - Bingyan Liu
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina
| | - Xiao Chen
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina
| | - Yunqiu Xie
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina
| | - Ling Ma
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina
| | - Yuanyuan Liu
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina
| | - Juan Chen
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina
| | - Huaxue Wang
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina
| | - Zhijun Li
- National Institute of Clinical Drug TrialsThe First Affiliated Hospital of Bengbu Medical CollegeBengbuAnhuiChina,The First Affiliated Hospital of Jinan UniversityGuangzhouGuangdongChina
| |
Collapse
|
|
18
|
Sriram H, Kunjachan F, Khanka T, Gawai S, Ghogale S, Deshpande N, Girase K, Patil J, Chatterjee G, Rajpal S, Patkar NV, Bagal B, Jain H, Sengar M, Hasan SK, Khattry N, Subramanian PG, Gujral S, Tembhare PR. Expression levels and patterns of B-cell maturation antigen in newly diagnosed and relapsed multiple myeloma patients from Indian subcontinent. CYTOMETRY. PART B, CLINICAL CYTOMETRY 2022; 102:462-470. [PMID: 36346307 DOI: 10.1002/cyto.b.22099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 09/16/2022] [Accepted: 10/18/2022] [Indexed: 11/09/2022]
Abstract
BACKGROUND Many novel therapies are being evaluated for the treatment of Multiple myeloma (MM). The cell-surface protein B-cell maturation antigen (BCMA, CD269) has recently emerged as a promising target for CAR-T cell and monoclonal-antibody therapies in MM. However, the knowledge of the BCMA expression-pattern in myeloma patients from the Indian subcontinent is still not available. We present an in-depth study of BCMA expression-pattern on abnormal plasma cells (aPC) in Indian MM patients. METHODS We studied BM samples from 217 MM patients (211-new and 6-relapsed) with a median age of 56 years (range, 30-78 years & M:F-2.29) and 20 control samples. Expression levels/patterns of CD269 (clone-19f2) were evaluated in aPCs from MM patients and in normal PCs (nPC) from uninvolved staging bone marrow samples (controls) using multicolor flow cytometry (MFC). Expression-level of CD269 was determined as a ratio of mean fluorescent intensity (MFI-R) of CD269 in PCs to that of non-B-lymphocytes and expression-pattern (homogenous/heterogeneous) as coefficient-of-variation of immunofluorescence (CVIF). RESULTS Median (range) percentage of CD269-positive abnormal-PCs in total PCs was 71.6% (0.49-99.29%). The MFI-R (median, range) of CD269 was significantly higher in aPCs (4.13, 1.12-26.88) than nPCs (3.33, 1.23-12.87), p < .0001. Median (range) MFI of CD269 at diagnosis and relapse were 2.39 (0.77-9.57) and 2.66 (2.15-3.23) respectively. CD269 levels were similar at diagnosis and relapse, p = .5529. CONCLUSIONS We demonstrated that BCMA/CD269 is highly expressed in aPCs from a majority of MM patients, both at diagnosis and relapse. Thus, BCMA is a valuable target for therapy for Indian MM patients.
Collapse
Affiliation(s)
- Harshini Sriram
- Hematopathology Laboratory, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Florence Kunjachan
- Hematopathology Laboratory, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Twinkle Khanka
- Hematopathology Laboratory, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Sangamitra Gawai
- Hematopathology Laboratory, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Sitaram Ghogale
- Hematopathology Laboratory, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Nilesh Deshpande
- Hematopathology Laboratory, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Karishma Girase
- Hematopathology Laboratory, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Jagruti Patil
- Hematopathology Laboratory, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Gaurav Chatterjee
- Hematopathology Laboratory, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Sweta Rajpal
- Hematopathology Laboratory, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Nikhil V Patkar
- Hematopathology Laboratory, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Bhausaheb Bagal
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Hasmukh Jain
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Manju Sengar
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Syed Khizer Hasan
- Cell and Tumor Biology Group, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Navin Khattry
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Papagudi G Subramanian
- Hematopathology Laboratory, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Sumeet Gujral
- Hematopathology Laboratory, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Prashant R Tembhare
- Hematopathology Laboratory, ACTREC, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| |
Collapse
|
|
19
|
Bolkun L, Tynecka M, Wasiluk T, Piszcz J, Starosz A, Grubczak K, Moniuszko M, Eljaszewicz A. A Proliferation-Inducing Ligand and B-Cell Activating Factor Are Upregulated in Patients with Essential Thrombocythemia. J Clin Med 2022; 11:jcm11164663. [PMID: 36012902 PMCID: PMC9409834 DOI: 10.3390/jcm11164663] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 08/01/2022] [Accepted: 08/04/2022] [Indexed: 12/20/2022] Open
Abstract
A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) are cytokines belonging to the tumor necrosis factor family which play an essential role in B-cell maturation, differentiation, and survival. Recent evidence indicates their importance in hematological disorders; however, their function in essential thrombocytosis (ET) pathogenesis remains elusive. Therefore, we aimed to analyze the role of APRIL and BAFF in megakaryocytopoiesis in ET patients. We observed elevated levels of APRIL and BAFF in the plasma of ET patients compared with healthy controls, while no differences were found among patients with different JAK2(V617F) statuses. In addition, APRIL levels were positively associated with the number of platelets and WBC count. In the bone marrow, APRIL but not BAFF levels were higher in ET patients with the JAK2(V617F) mutation; however, JAK2(V617F)-negative patients showed slightly reduced levels of BAFF. In ET patients, we showed that the differentiation of CD34+ progenitor cells towards megakaryocytes induces the expression of both APRIL and BAFF. More importantly, APRIL neutralization significantly reduced platelet production. In conclusion, our data provide evidence that blocking APRIL signaling, which acts as an autocrine growth factor for terminal megakaryocytopoiesis, inhibits platelet production in ET patients, regardless of the status of JAK2(V617F) mutation.
Collapse
Affiliation(s)
- Lukasz Bolkun
- Department of Haematology, Medical University of Bialystok, ul. M. Skłodowskiej-Curie 24A, 15-276 Bialystok, Poland
- Correspondence: (L.B.); (A.E.); Tel.: +48-85-7468230 (L.B.); +48-85-748-59-72 (A.E.); Fax: +48-85-748-59-71 (A.E.)
| | - Marlena Tynecka
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269 Bialystok, Poland
| | - Tomasz Wasiluk
- Regional Centre for Transfusion Medicine, Bialystok, ul. M. Skłodowskiej-Curie 23, 15-950 Bialystok, Poland
| | - Jaroslaw Piszcz
- Department of Haematology, Medical University of Bialystok, ul. M. Skłodowskiej-Curie 24A, 15-276 Bialystok, Poland
| | - Aleksandra Starosz
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269 Bialystok, Poland
| | - Kamil Grubczak
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269 Bialystok, Poland
| | - Marcin Moniuszko
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269 Bialystok, Poland
- Department of Allergology and Internal Medicine, Medical University of Bialystok, ul. M. Skłodowskiej-Curie 24A, 15-276 Bialystok, Poland
| | - Andrzej Eljaszewicz
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269 Bialystok, Poland
- Correspondence: (L.B.); (A.E.); Tel.: +48-85-7468230 (L.B.); +48-85-748-59-72 (A.E.); Fax: +48-85-748-59-71 (A.E.)
| |
Collapse
|
|
20
|
Zhou H, Dong Y, Alhaskawi A, Lai J, Wang Z, Ezzi SHA, Kota VG, Abdulla MHAH, Sun Z, Lu H. The Roles of TNF Signaling Pathways in Metabolism of Bone Tumors. Front Pharmacol 2022; 13:907629. [PMID: 35847045 PMCID: PMC9277014 DOI: 10.3389/fphar.2022.907629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 05/30/2022] [Indexed: 12/15/2022] Open
Abstract
The metabolism of bone tumors is extraordinarily complex and involves many signaling pathways and processes, including the tumor necrosis factor (TNF) signaling pathway, which consists of TNF factors and the TNF receptors that belong to the TNF receptor superfamily (TNFRSF). It is appreciated that signaling events and pathways involving TNFRSF components are essential in coordinating the functions of multiple cell types that act as a host defense network against pathogens and malignant cells, the implications of TNFRSF-related signaling pathways on bone tumor metabolism remain to be summarized, which is one of the significant obstacles to the application of TNF-related treatment modalities in the domain of bone oncology. This review will discuss and summarize the anti-tumor properties of important TNFRSF components concerning osteosarcoma, chondrosarcoma, and Ewing sarcoma.
Collapse
Affiliation(s)
- Haiying Zhou
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Yanzhao Dong
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Ahmad Alhaskawi
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Jingtian Lai
- Zhejiang University School of Medicine, Hangzhou, China
| | - Zewei Wang
- Zhejiang University School of Medicine, Hangzhou, China
| | | | | | | | - Zhenyu Sun
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Hui Lu
- Department of Orthopedics, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
- Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Zhejiang University, Hangzhou, China
| |
Collapse
|
|
21
|
Ferreira BV, Carneiro EA, Pestana C, Barahona F, Caetano J, Lopes R, Lúcio P, Neves M, Beck HC, Carvalho AS, Matthiesen R, Costa-Silva B, João C. Patient-Derived Extracellular Vesicles Proteins as New Biomarkers in Multiple Myeloma - A Real-World Study. Front Oncol 2022; 12:860849. [PMID: 35800053 PMCID: PMC9254863 DOI: 10.3389/fonc.2022.860849] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 05/16/2022] [Indexed: 12/14/2022] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy of clonal antibody–secreting plasma cells (PCs). MM diagnosis and risk stratification rely on bone marrow (BM) biopsy, an invasive procedure prone to sample bias. Liquid biopsies, such as extracellular vesicles (EV) in peripheral blood (PB), hold promise as new minimally invasive tools. Real-world studies analyzing patient-derived EV proteome are rare. Here, we characterized a small EV protein content from PB and BM samples in a cohort of 102 monoclonal gammopathies patients routinely followed in the clinic and 223 PB and 111 BM samples were included. We investigated whether EV protein and particle concentration could predict an MM patient prognosis. We found that a high EV protein/particle ratio, or EV cargo >0.6 µg/108 particles, is related to poorer survival and immune dysfunction. These results were supported at the protein level by mass spectrometry. We report a set of PB EV-proteins (PDIA3, C4BPA, BTN1A1, and TNFSF13) with a new biomarker potential for myeloma patient outcomes. The high proteomic similarity between PB and BM matched pairs supports the use of circulating EV as a counterpart of the BM EV proteome. Overall, we found that the EV protein content is related to patient outcomes, such as survival, immune dysfunction, and possibly treatment response.
Collapse
Affiliation(s)
- Bruna Velosa Ferreira
- Myeloma Lymphoma Research Group, Champalimaud Experimental Clinical Research Programme, Champalimaud Foundation, Lisbon, Portugal
- NOVA Medical School (NMS), NOVA University Lisbon, Lisbon, Portugal
- Hemato-Oncology Unit, Champalimaud Clinical Centre, Champalimaud Foundation, Lisbon, Portugal
| | - Emilie Arnault Carneiro
- Myeloma Lymphoma Research Group, Champalimaud Experimental Clinical Research Programme, Champalimaud Foundation, Lisbon, Portugal
| | - Carolina Pestana
- Myeloma Lymphoma Research Group, Champalimaud Experimental Clinical Research Programme, Champalimaud Foundation, Lisbon, Portugal
- Centre of Statistics and its Applications, Faculty of Sciences, University of Lisbon, Lisbon, Portugal
| | - Filipa Barahona
- Myeloma Lymphoma Research Group, Champalimaud Experimental Clinical Research Programme, Champalimaud Foundation, Lisbon, Portugal
- NOVA Medical School (NMS), NOVA University Lisbon, Lisbon, Portugal
| | - Joana Caetano
- Myeloma Lymphoma Research Group, Champalimaud Experimental Clinical Research Programme, Champalimaud Foundation, Lisbon, Portugal
- NOVA Medical School (NMS), NOVA University Lisbon, Lisbon, Portugal
- Hemato-Oncology Unit, Champalimaud Clinical Centre, Champalimaud Foundation, Lisbon, Portugal
| | - Raquel Lopes
- Myeloma Lymphoma Research Group, Champalimaud Experimental Clinical Research Programme, Champalimaud Foundation, Lisbon, Portugal
- Faculty of Medicine, University of Lisbon, Lisbon, Portugal
| | - Paulo Lúcio
- Hemato-Oncology Unit, Champalimaud Clinical Centre, Champalimaud Foundation, Lisbon, Portugal
| | - Manuel Neves
- Hemato-Oncology Unit, Champalimaud Clinical Centre, Champalimaud Foundation, Lisbon, Portugal
| | - Hans Christian Beck
- Centre for Clinical Proteomics, Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark
| | - Ana Sofia Carvalho
- NOVA Medical School (NMS), Faculdade de Ciências Médicas (FCM), Universidade Nova de Lisboa, Lisboa, Portugal
| | - Rune Matthiesen
- NOVA Medical School (NMS), Faculdade de Ciências Médicas (FCM), Universidade Nova de Lisboa, Lisboa, Portugal
| | - Bruno Costa-Silva
- Systems Oncology Group, Champalimaud Physiology and Cancer Programme, Champalimaud Foundation, Lisbon, Portugal
- *Correspondence: Bruno Costa-Silva, ; Cristina João,
| | - Cristina João
- Myeloma Lymphoma Research Group, Champalimaud Experimental Clinical Research Programme, Champalimaud Foundation, Lisbon, Portugal
- NOVA Medical School (NMS), NOVA University Lisbon, Lisbon, Portugal
- Hemato-Oncology Unit, Champalimaud Clinical Centre, Champalimaud Foundation, Lisbon, Portugal
- *Correspondence: Bruno Costa-Silva, ; Cristina João,
| |
Collapse
|
|
22
|
Watson E, Djebbari F, Rampotas A, Ramasamy K. BCMA-targeted therapies for multiple myeloma: strategies to maximise efficacy and minimize adverse events. Expert Rev Hematol 2022; 15:503-517. [PMID: 35633050 DOI: 10.1080/17474086.2022.2084068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Immunotherapies targeting B cell maturation antigen (BCMA) in multiple myeloma are transitioning through trials and entering the clinic, and will likely become a core pillar in myeloma therapeutics. These agents demonstrate unprecedented activity in multiply relapsed patients, but - notwithstanding the short follow-up times - their survival curves do not appear to demonstrate a plateau, and the treatments inevitably bring with them a range of toxicities that might be associated with tolerability issues. AREAS COVERED We will briefly lay out the current therapeutic landscape in multiple myeloma, before introducing BCMA and explaining its significance. We will address in turn the three key classes of anti-BCMA immunotherapies: antibody-drug conjugates, bispecific antibodies and chimeric antigen receptor T cells. We describe the mechanisms of action of these classes and review the evidence supporting their efficacy and toxicities. We then bring all three therapies into one discussion that explores how to mitigate toxicities and overcome myeloma's ability to resist these potent treatments. EXPERT OPINION Finally, we take the discussion back to the clinic, and consider how we might deploy anti-BCMA therapies most effectively for our patients. We consider the sequencing of treatment, and what further evidence is needed to more fully inform our therapy decisions.
Collapse
Affiliation(s)
- Edmund Watson
- Clinical Haematology Department, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Old Road, Oxford, OX3 7LE, UK
| | - Faouzi Djebbari
- Clinical Haematology Department, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Old Road, Oxford, OX3 7LE, UK
| | - Alexandros Rampotas
- Clinical Haematology Department, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Old Road, Oxford, OX3 7LE, UK
| | - Karthik Ramasamy
- Clinical Haematology Department, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Old Road, Oxford, OX3 7LE, UK
| |
Collapse
|
|
23
|
Parodis I, Gomez A, Lindblom J, Chow JW, Doria A, Gatto M. Early Changes in B and Plasma Cell Subsets and Traditional Serological Markers as Predictors of SRI-4 Response to Therapy in Systemic Lupus Erythematosus. Front Med (Lausanne) 2022; 9:852162. [PMID: 35572992 PMCID: PMC9096349 DOI: 10.3389/fmed.2022.852162] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 04/05/2022] [Indexed: 01/13/2023] Open
Abstract
Objective With the premise of the hypothesis that early biological responses to therapy for active systemic lupus erythematosus (SLE) portend later clinical improvements, we studied changes in B cell subsets and traditional serological markers in relation to clinical response to standard therapy (ST) with or without the addition of belimumab. Patients and Methods We analyzed data from the BLISS-76, BLISS-SC, and BLISS Northeast Asia trials (N = 1712). Circulating CD19+ B cell subsets were determined by flow-cytometry. We studied associations of relative to baseline percentage changes in circulating B and plasma cell subsets, anti-dsDNA antibody levels and complement levels with SLE Responder Index (SRI)-4 response after 52 weeks of treatment. Changes occurring through week 8 were deemed "rapid," through week 24 "early," and thereafter "delayed". Results In the analysis of the entire cohort, SRI-4 responders showed more prominent decreases from baseline through week 52 in CD19+CD20+CD27- naïve B cells (median change: -61.2% versus -50.0%; P = 0.004), CD19+CD20-CD27 bright plasmablasts (-44.9% versus -33.3%; P = 0.011), and CD19+CD20-CD138+ long-lived plasma cells (-48.2% versus -37.1%; P = 0.024), and a more prominent rapid (+92.0% versus +66.7%; P = 0.002) and early (+60.0% versus +49.5%; P = 0.033) expansion of CD19+CD20+CD27+ memory B cells than non-responders. More prominent rapid reductions in anti-dsDNA (-14.8% versus -8.7%; P = 0.043) and increases in C3 (+4.9% versus +2.1%; P = 0.014) and C4 levels (+11.5% versus +8.3%; P = 0.017) were documented in SRI-4 responders compared with non-responders among patients who received add-on belimumab, but not among patients who received non-biological ST alone. Conclusion SRI-4 responders showed a more prominent rapid expansion of memory B cells and more prominent delayed reductions in naïve B cells, plasmablasts and long-lived plasma cells. Moreover, clinical response to belimumab was associated with preceding more prominent reductions of anti-dsDNA and increases in C3 and C4 levels. Monitoring biological changes may prove useful in SLE patient surveillance and early treatment evaluation.
Collapse
Affiliation(s)
- Ioannis Parodis
- Division of Rheumatology, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.,Department of Rheumatology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Alvaro Gomez
- Division of Rheumatology, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Julius Lindblom
- Division of Rheumatology, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Jun Weng Chow
- Division of Rheumatology, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Andrea Doria
- Unit of Rheumatology, Department of Medicine, University of Padua, Padua, Italy
| | - Mariele Gatto
- Unit of Rheumatology, Department of Medicine, University of Padua, Padua, Italy
| |
Collapse
|
|
24
|
Zerdan MB, Nasr L, Kassab J, Saba L, Ghossein M, Yaghi M, Dominguez B, Chaulagain CP. Adhesion molecules in multiple myeloma oncogenesis and targeted therapy. Int J Hematol Oncol 2022; 11:IJH39. [PMID: 35663420 PMCID: PMC9136637 DOI: 10.2217/ijh-2021-0017] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 04/07/2022] [Indexed: 11/21/2022] Open
Abstract
Every day we march closer to finding the cure for multiple myeloma. The myeloma cells inflict their damage through specialized cellular meshwork and cytokines system. Implicit in these interactions are cellular adhesion molecules and their regulators which include but are not limited to integrins and syndecan-1/CD138, immunoglobulin superfamily cell adhesion molecules, such as CD44, cadherins such as N-cadherin, and selectins, such as E-selectin. Several adhesion molecules are respectively involved in myelomagenesis such as in the transition from the precursor disorder monoclonal gammopathy of undetermined significance to indolent asymptomatic multiple myeloma (smoldering myeloma) then to active multiple myeloma or primary plasma cell leukemia, and in the pathological manifestations of multiple myeloma.
Collapse
Affiliation(s)
- Maroun Bou Zerdan
- Department of Hematology-Oncology, Myeloma & Amyloidosis Program, Maroone Cancer Center, Cleveland Clinic Florida, Weston, FL 33331, USA
| | - Lewis Nasr
- Saint-Joseph University, Faculty of Medicine, Beirut, Lebanon
| | - Joseph Kassab
- Saint-Joseph University, Faculty of Medicine, Beirut, Lebanon
| | - Ludovic Saba
- Saint-Joseph University, Faculty of Medicine, Beirut, Lebanon
| | - Myriam Ghossein
- Department of Medicine & Medical Sciences, University of Balamand, Balamand, Lebanon
| | - Marita Yaghi
- Department of Hematology-Oncology, Myeloma & Amyloidosis Program, Maroone Cancer Center, Cleveland Clinic Florida, Weston, FL 33331, USA
| | - Barbara Dominguez
- Department of Hematology-Oncology, Myeloma & Amyloidosis Program, Maroone Cancer Center, Cleveland Clinic Florida, Weston, FL 33331, USA
| | - Chakra P Chaulagain
- Department of Hematology-Oncology, Myeloma & Amyloidosis Program, Maroone Cancer Center, Cleveland Clinic Florida, Weston, FL 33331, USA
| |
Collapse
|
|
25
|
Guo R, Lu W, Zhang Y, Cao X, Jin X, Zhao M. Targeting BCMA to Treat Multiple Myeloma: Updates From the 2021 ASH Annual Meeting. Front Immunol 2022; 13:839097. [PMID: 35320942 PMCID: PMC8936073 DOI: 10.3389/fimmu.2022.839097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 02/07/2022] [Indexed: 11/24/2022] Open
Abstract
With the gradual improvement of treatment regimens, the survival time of multiple myeloma (MM) patients has been significantly prolonged. Even so, MM is still a nightmare with an inferior prognosis. B-cell maturation antigen (BCMA) is highly expressed on the surface of malignant myeloma cells. For the past few years, significant progress has been made in various BCMA-targeted immunotherapies for treating patients with RRMM, including anti-BCMA mAbs, antibody-drug conjugates, bispecific T-cell engagers, and BCMA-targeted adoptive cell therapy like chimeric antigen receptor (CAR)-T cell. The 63rd annual meeting of the American Society of Hematology updated some information about the application of BCMA in MM. This review summarizes part of the related points presented at this conference.
Collapse
Affiliation(s)
- Ruiting Guo
- First Center Clinic College of Tianjin Medical University, Tianjin, China
| | - Wenyi Lu
- Department of Hematology, Tianjin First Central Hospital, Tianjin, China
| | - Yi Zhang
- First Center Clinic College of Tianjin Medical University, Tianjin, China
| | - Xinping Cao
- First Center Clinic College of Tianjin Medical University, Tianjin, China
| | - Xin Jin
- Department of Hematology, Tianjin First Central Hospital, Tianjin, China
| | - Mingfeng Zhao
- Department of Hematology, Tianjin First Central Hospital, Tianjin, China
| |
Collapse
|
|
26
|
Nobari ST, Nojadeh JN, Talebi M. B-cell maturation antigen targeting strategies in multiple myeloma treatment, advantages and disadvantages. J Transl Med 2022; 20:82. [PMID: 35144648 PMCID: PMC8832753 DOI: 10.1186/s12967-022-03285-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 01/29/2022] [Indexed: 01/02/2023] Open
Abstract
B cell maturation antigen (BCMA), a transmembrane glycoprotein member of the tumor necrosis factor receptor superfamily 17 (TNFRSF17), highly expressed on the plasma cells of Multiple myeloma (MM) patients, as well as the normal population. BCMA is used as a biomarker for MM. Two members of the TNF superfamily proteins, including B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL), are closely related to BCMA and play an important role in plasma cell survival and progression of MM. Despite the maximum specificity of the monoclonal antibody technologies, introducing the tumor-specific antigen(s) is not applicable for all malignancies, such as MM that there plenty of relatively specific antigens such as GPCR5D, MUC1, SLAMF7 and etc., but higher expression of BCMA on these cells in comparison with normal ones can be regarded as a relatively exclusive marker. Currently, different monoclonal antibody (mAb) technologies applied in anti-MM therapies such as daratuzumab, SAR650984, GSK2857916, and CAR-T cell therapies are some of these tools that are reviewed in the present manuscript. By the way, the structure, function, and signaling of the BCMA and related molecule(s) role in normal plasma cells and MM development, evaluated as well as the potential side effects of its targeting by different CAR-T cells generations. In conclusion, BCMA can be regarded as an ideal molecule to be targeted in immunotherapeutic methods, regarding lower potential systemic and local side effects.
Collapse
Affiliation(s)
- Shirin Teymouri Nobari
- Department of Medical Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Jafar Nouri Nojadeh
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Talebi
- Department of Applied Cells Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
27
|
Quazi S. An Overview of CAR T Cell Mediated B Cell Maturation Antigen Therapy. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2022; 22:e392-e404. [PMID: 34992008 DOI: 10.1016/j.clml.2021.12.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 11/30/2021] [Accepted: 12/06/2021] [Indexed: 12/24/2022]
Abstract
Multiple Myeloma (MM) is one of the incurable types of cancer in plasma cells. While immense progress has been made in the treatment of this malignancy, a large percentage of patients were unable to adapt to such therapy. Additionally, these therapies might be associated with significant diseases and are not always tolerated well in all patients. Since cancer in plasma cells has no cure, patients develop resistance to treatments, resulting in R/R MM (Refractory/Relapsed Multiple Myeloma). BCMA (B cell maturation antigen) is primarily produced on mature B cells. It's up-regulation and activation are associated with multiple myeloma in both murine and human models, indicating that this might be an effective therapeutic target for this type of malignancy. Additionally, BCMA's predictive value, association with effective clinical trials, and capacity to be utilized in previously difficult to observe patient populations, imply that it might be used as a biomarker for multiple myeloma. Numerous kinds of BCMA-targeting medicines have demonstrated antimyeloma efficacy in individuals with refractory/relapsed MM, including CAR T-cell (Chimeric antigen receptor T cell) treatments, ADCs (Antibody-drug conjugate s), bispecific antibody constructs. Among these medications, CART cell-mediated BCMA therapy has shown significant outcomes in multiple myeloma clinical trials. This review article outlines CAR T cell mediated BCMA medicines have the efficiency to change the therapeutic pattern for multiple myeloma significantly.
Collapse
Affiliation(s)
- Sameer Quazi
- GenLab Biosolutions Private Limited, Bangalore, Karnataka, India.
| |
Collapse
|
|
28
|
Swan D, Routledge D, Harrison S. The evolving status of immunotherapies in multiple myeloma: the future role of bispecific antibodies. Br J Haematol 2021; 196:488-506. [PMID: 34472091 DOI: 10.1111/bjh.17805] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 08/16/2021] [Indexed: 12/18/2022]
Abstract
Treatment outcomes in multiple myeloma (MM) have improved dramatically over the past 10 years. However, patients with high-risk disease such as those with Stage III disease by the Revised International Staging System, the presence of adverse cytogenetics, or who are refractory to proteosome inhibitors, immunomodulatory drugs and monoclonal antibodies may have dismal outcomes. These patients represent an urgent ongoing need in MM. One of the hallmarks of MM is immune dysfunction and a tumour-permissive immune microenvironment. Ameliorating the immune-paresis could lead to improved outcomes. The role of immunotherapies has been growing at an exponential pace with numerous agents under development in clinical trials. In the present review, we provide an overview of immunotherapies in MM, focussing on bispecific antibodies (BsAbs). We review efficacy outcomes from the published clinical trials and consider the important safety aspects of these therapies, in particular the risk of cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome, and how these compare with patients receiving chimeric antigen receptor T cells. We discuss the MM epitopes being targeted by BsAbs, either in clinical or preclinical stages, and we consider where these therapies might best fit within the future ever-changing paradigm of MM treatment.
Collapse
Affiliation(s)
- Dawn Swan
- Department of Haematology, St James' Hospital, Dublin, Ireland
| | - David Routledge
- Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia
| | - Simon Harrison
- Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia
| |
Collapse
|
|
29
|
Mohyuddin GR, Banerjee R, Alam Z, Berger KE, Chakraborty R. Rethinking mechanisms of neurotoxicity with BCMA directed therapy. Crit Rev Oncol Hematol 2021; 166:103453. [PMID: 34461271 DOI: 10.1016/j.critrevonc.2021.103453] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 08/09/2021] [Accepted: 08/10/2021] [Indexed: 11/26/2022] Open
Abstract
B-cell maturation antigen (BCMA) has become a key target for antibody-drug conjugates, bispecific antibodies, chimeric antigen receptor T-cell therapies, and other immunotherapies in multiple myeloma. Some of these agents such as belantamab mafodotin and idecabtagene vicleucel have already received regulatory approval in the United States. Although BCMA has generally been considered to be expressed almost exclusively in plasma cells with a low likelihood of on-target off-tumor toxicity, there has been a range of unusual neurotoxicity observed across the spectrum of BCMA immunotherapies. In certain cases, these unusual neurotoxicity presentations have led to patient death or withdrawal of agents from further development. Our review summarizes the literature in this field and highlights the possibility of on-target toxicities due to neural expression of BCMA. We draw attention to the need for further investigation of these toxicities. This risk becomes increasingly important as BCMA targeted therapies are brought to earlier lines of treatment.
Collapse
Affiliation(s)
- Ghulam Rehman Mohyuddin
- Department of Hematology and Hematological Malignancies, Huntsman Cancer Center, University of Utah, United States.
| | - Rahul Banerjee
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, United States
| | - Zakariya Alam
- Department of Neurology, University of Massachusetts, United States
| | - Katherine E Berger
- University of Hartford, 200 Bloomfield Ave, West Hartford, CT 06117, United States
| | | |
Collapse
|
|
30
|
Nowacka KH, Jabłońska E. Role of the APRIL molecule in solid tumors. Cytokine Growth Factor Rev 2021; 61:38-44. [PMID: 34446365 DOI: 10.1016/j.cytogfr.2021.08.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/11/2021] [Accepted: 08/14/2021] [Indexed: 10/20/2022]
Abstract
The APRIL molecule, produced by immune cells, their precursors, and cancer cells, is one of the important factors that influences the process of survival and proliferation of cancer cells. In the present review, we summarize the current knowledge on the effects of APRIL on human cancer development and develop a scheme demonstrating the mechanism of the action of APRIL on solid tumors. Understanding the effects of APRIL, including the intracellular signal transduction pathway, may be key for the use of this protein as a biomarker of the cancer process. The correlations observed between APRIL levels and cancer parameters (e.g., disease stage and presence of malignant phenotypes) indicate that APRIL may play an important role, not only in the diagnostic process, but also as a therapeutic target in various cancers.
Collapse
Affiliation(s)
- Kinga Henryka Nowacka
- Department of Immunology, Medical University of Bialystok, J. Waszyngtona 15A, 15-269 Białystok, Poland.
| | - Ewa Jabłońska
- Department of Immunology, Medical University of Bialystok, J. Waszyngtona 15A, 15-269 Białystok, Poland.
| |
Collapse
|
|
31
|
Offidani M, Corvatta L, Morè S, Olivieri A. Belantamab Mafodotin for the Treatment of Multiple Myeloma: An Overview of the Clinical Efficacy and Safety. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:2401-2415. [PMID: 34103900 PMCID: PMC8180291 DOI: 10.2147/dddt.s267404] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 04/10/2021] [Indexed: 12/20/2022]
Abstract
Despite the introduction of immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and, more recently, monoclonal antibodies (mAbs), in the chemotherapy regimens for newly diagnosed (NDMM) and relapsed/refractory MM (RRMM), the occurrence of drug resistance remains a challenge in MM patients. This is mainly in the advanced stage of the disease when treatments are limited, and the prognosis is abysmal. Nevertheless, novel molecules and therapeutic approaches are rapidly moving through the several phases of drug development and could address the need for new treatment options. The recent innovative B-cell maturation antigen (BCMA) targeted immunotherapies, such as belantamab mafodotin, the first-in-class monoclonal antibody-drug conjugate (ADC), induce an effective and durable response in triple-class refractory disease and to be approved in MM. In contrast with the other BCMA-targeted therapies as CAR T cells with a complex manufacturing process, and bispecific antibodies, both requiring inpatient hospitalization to monitor the occurrence of severe adverse events, belantamab mafodotin is an “off-the-shelf” drug that can be administered in an outpatient setting. Many belantamab mafodotin-based combinations are under evaluation in Phase I, II, and III clinical trials either late or in early RRMM patients. Ocular toxicity represents a peculiar side effect of belantamab mafodotin. This toxicity is generally manageable with adequate dose reductions or delays since most patients who developed keratopathy recovered on treatment and discontinued ADC are rare. Here, we described the most recent clinical data of belantamab mafodotin and discussed the possible leading role of this intriguing agent in the near future of MM treatment.
Collapse
Affiliation(s)
- Massimo Offidani
- Clinica di Ematologia Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Ancona, Ancona, Italy
| | | | - Sonia Morè
- Clinica di Ematologia Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Ancona, Ancona, Italy
| | - Attilio Olivieri
- Clinica di Ematologia Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Ancona, Ancona, Italy
| |
Collapse
|
|
32
|
Kumar G, Maria Z, Kohli U, Agasing A, Quinn JL, Ko RM, Zamvil SS, Axtell RC. CNS Autoimmune Responses in BCMA-Deficient Mice Provide Insight for the Failure of Atacicept in MS. NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION 2021; 8:8/3/e973. [PMID: 33649164 PMCID: PMC7954465 DOI: 10.1212/nxi.0000000000000973] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 12/21/2020] [Indexed: 11/15/2022]
Abstract
OBJECTIVE B cells have emerged as a therapeutic target for MS. Anti-CD20 antibodies, which deplete B cells, are effective therapies for MS. However, atacicept (TACI-Fc), which blocks BAFF and APRIL and reduces B cells, unexpectedly exacerbates MS. We tested the hypothesis that B cell maturation antigen (BCMA), a receptor for BAFF and APRIL, plays a role in the paradoxical effects of anti-CD20 antibody and TACI-Fc using experimental autoimmune encephalomyelitis (EAE). METHODS EAE was induced in wild-type (BCMA+/+) and BCMA-deficient (BCMA-/-) mice with an immunization of rodent myelin oligodendrocyte glycoprotein (MOG)35-55 peptide. Treatment with anti-CD20 antibody, TACI-Fc, and isotype controls was administered by intraperitoneal injections. CNS infiltration was evaluated by histology; immune cell phenotypes were evaluated by flow cytometry; MOG-specific antibodies were determined by ELISA. Mixed bone marrow chimeras and cell culture assays were used to identify the specific subsets of immune cells affected by BCMA deficiency. RESULTS First, we found that BCMA-/- mice had more severe EAE compared with BCMA+/+ mice and the increased disease was associated with elevated anti-MOG B-cell responses. Second, we found that anti-CD20 therapy attenuated EAE in BCMA-/- mice but not in BCMA+/+ mice. Third, TACI-Fc attenuated EAE in BCMA+/+ mice but not in BCMA-/- mice. Mixed bone marrow chimeric and cell culture experiments demonstrated that BCMA deficiency elevates inflammatory B-cell responses but inhibits inflammatory responses in macrophages. CONCLUSIONS BCMA has multifaceted roles during inflammation that affects therapeutic efficacies of anti-CD20 and TACI-Fc in EAE. Our results from BCMA-deficient mice provide insights into the failure of atacicept in MS.
Collapse
Affiliation(s)
- Gaurav Kumar
- From the ACI (G.K., Z.M., U.K., A.A., J.L.Q., R.M.K., R.C.A.), Oklahoma Medical Research Foundation; and Department of Neurology and Program in Immunology, (S.S.Z.), University of California San Francisco
| | - Zahra Maria
- From the ACI (G.K., Z.M., U.K., A.A., J.L.Q., R.M.K., R.C.A.), Oklahoma Medical Research Foundation; and Department of Neurology and Program in Immunology, (S.S.Z.), University of California San Francisco
| | - Uday Kohli
- From the ACI (G.K., Z.M., U.K., A.A., J.L.Q., R.M.K., R.C.A.), Oklahoma Medical Research Foundation; and Department of Neurology and Program in Immunology, (S.S.Z.), University of California San Francisco
| | - Agnieshka Agasing
- From the ACI (G.K., Z.M., U.K., A.A., J.L.Q., R.M.K., R.C.A.), Oklahoma Medical Research Foundation; and Department of Neurology and Program in Immunology, (S.S.Z.), University of California San Francisco
| | - James L Quinn
- From the ACI (G.K., Z.M., U.K., A.A., J.L.Q., R.M.K., R.C.A.), Oklahoma Medical Research Foundation; and Department of Neurology and Program in Immunology, (S.S.Z.), University of California San Francisco
| | - Rose M Ko
- From the ACI (G.K., Z.M., U.K., A.A., J.L.Q., R.M.K., R.C.A.), Oklahoma Medical Research Foundation; and Department of Neurology and Program in Immunology, (S.S.Z.), University of California San Francisco
| | - Scott S Zamvil
- From the ACI (G.K., Z.M., U.K., A.A., J.L.Q., R.M.K., R.C.A.), Oklahoma Medical Research Foundation; and Department of Neurology and Program in Immunology, (S.S.Z.), University of California San Francisco
| | - Robert C Axtell
- From the ACI (G.K., Z.M., U.K., A.A., J.L.Q., R.M.K., R.C.A.), Oklahoma Medical Research Foundation; and Department of Neurology and Program in Immunology, (S.S.Z.), University of California San Francisco.
| |
Collapse
|
|
33
|
Martino M, Paviglianiti A. An update on B-cell maturation antigen-targeted therapies in Multiple Myeloma. Expert Opin Biol Ther 2021; 21:1025-1034. [PMID: 33412948 DOI: 10.1080/14712598.2021.1872540] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Introduction: B-cell maturation antigen (BCMA) targeted therapy (BCMA-TT) has emerged as a promising treatment for Multiple Myeloma (MM). the three most common treatment modalities for targeting BCMA are antibody-drug conjugates (ADCs), bispecific antibody constructs, including BiTE (bispecific T-cell engager) immuno-oncology therapies, and chimeric antigen receptor (CAR)-modified T-cell therapy.Areas covered: The review provides an overview of the main published studies on clinical and pre-clinical data from trials using BCMA-TT.Expert opinion: Despite progresses in survival outcomes and the availability of new drugs, MM remains an incurable disease. ADC is a promising antibody-based treatment and Belantamab mafodotin showed an anti-myeloma effect alone or in combination with other drugs. The major issue of ADC is the occurrence of events interfering with the efficacy and the off-target cytotoxicity. Bispecific antibody constructs are off-the-shelf therapies characterized by a potential rapid availability. The most critical limitation of bispecific antibody constructs is their short half-life necessitating prolonged intravenous infusion. CAR-T cells produced unprecedented results in heavily pretreated RRMM. The most common toxicities include neurologic toxicity and cytokine release syndrome, B-cell aplasia, cytopenias, and hypogammaglobulinemia. Further studies are needed to detect which are the eligible patients who could benefit from one treatment more than another.
Collapse
Affiliation(s)
- Massimo Martino
- Stem Cell Transplant and Cellular Therapies Unit, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy
| | - Annalisa Paviglianiti
- Stem Cell Transplant and Cellular Therapies Unit, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy
| |
Collapse
|
|
34
|
Gilly A, Park YC, Png G, Barysenka A, Fischer I, Bjørnland T, Southam L, Suveges D, Neumeyer S, Rayner NW, Tsafantakis E, Karaleftheri M, Dedoussis G, Zeggini E. Whole-genome sequencing analysis of the cardiometabolic proteome. Nat Commun 2020; 11:6336. [PMID: 33303764 PMCID: PMC7729872 DOI: 10.1038/s41467-020-20079-2] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 10/26/2020] [Indexed: 12/14/2022] Open
Abstract
The human proteome is a crucial intermediate between complex diseases and their genetic and environmental components, and an important source of drug development targets and biomarkers. Here, we comprehensively assess the genetic architecture of 257 circulating protein biomarkers of cardiometabolic relevance through high-depth (22.5×) whole-genome sequencing (WGS) in 1328 individuals. We discover 131 independent sequence variant associations (P < 7.45 × 10-11) across the allele frequency spectrum, all of which replicate in an independent cohort (n = 1605, 18.4x WGS). We identify for the first time replicating evidence for rare-variant cis-acting protein quantitative trait loci for five genes, involving both coding and noncoding variation. We construct and validate polygenic scores that explain up to 45% of protein level variation. We find causal links between protein levels and disease risk, identifying high-value biomarkers and drug development targets.
Collapse
Affiliation(s)
- Arthur Gilly
- Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
| | - Young-Chan Park
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
- University of Cambridge, Cambridge, UK
| | - Grace Png
- Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
| | - Andrei Barysenka
- Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
| | - Iris Fischer
- Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
| | - Thea Bjørnland
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
- Department of Mathematical Sciences, Norwegian University of Science and Technology, NO-7491, Trondheim, Norway
| | - Lorraine Southam
- Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
- Wellcome Centre for Human Genetics, Oxford, UK
| | - Daniel Suveges
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
- European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, CB10 1SH, UK
| | - Sonja Neumeyer
- Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
| | - N William Rayner
- Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | | | | | - George Dedoussis
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Moschato, Greece
| | - Eleftheria Zeggini
- Institute of Translational Genomics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK.
- TUM School of Medicine, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany.
| |
Collapse
|
|
35
|
Rodríguez-Otero P, Prósper F, Alfonso A, Paiva B, Miguel JFS. CAR T-Cells in Multiple Myeloma Are Ready for Prime Time. J Clin Med 2020; 9:E3577. [PMID: 33172026 PMCID: PMC7694626 DOI: 10.3390/jcm9113577] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 10/30/2020] [Accepted: 11/02/2020] [Indexed: 01/22/2023] Open
Abstract
The survival of patients with multiple myeloma (MM) has been dramatically improved in the last decade thanks to the incorporation of second-generation proteasome inhibitors (PI), immunomodulatory drugs (IMID), and, more recently, anti-CD38 monoclonal antibodies (MoAb). Nevertheless, still, a major proportion of MM patients will relapse, underscoring the need for new therapies in this disease. Moreover, survival in patients failing the current standard of care regimens (including PI, IMIDs, and anti-CD38 MoAb), which is now defined as triple-class refractory, remains dismal, and new drugs with different mechanism of action are needed. B-cell maturation antigen (BCMA)-targeted therapies and in particular chimeric antigen receptor T cell (CAR T-cell) treatment have emerged as promising platforms to overcome refractoriness to conventional drugs. In this manuscript, we review the current available data regarding CAR T-cell therapy for MM, with a special focus on target selection, clinical results, limitations, and future strategies.
Collapse
Affiliation(s)
- Paula Rodríguez-Otero
- Clínica Universidad de Navarra, Centro de investigación médica aplicada (Cima), CIBERONC, IDISNA, 31008 Pamplona, Spain; (F.P.); (A.A.); (B.P.); (J.F.S.M.)
| | | | | | | | | |
Collapse
|
|
36
|
APRIL-producing eosinophils are involved in gastric MALT lymphomagenesis induced by Helicobacter sp infection. Sci Rep 2020; 10:14858. [PMID: 32908188 PMCID: PMC7481773 DOI: 10.1038/s41598-020-71792-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 08/03/2020] [Indexed: 12/17/2022] Open
Abstract
The roles of the inflammatory response and production of a proliferation-inducing ligand (APRIL) cytokine in gastric mucosa-associated lymphoid tissue (MALT) lymphomagenesis induced by Helicobacter species infection are not clearly understood. We characterized the gastric mucosal inflammatory response associated with gastric MALT lymphoma (GML) and identified APRIL-producing cells in two model systems: an APRIL transgenic mouse model of GML induced by Helicobacter infection (Tg-hAPRIL) and human gastric biopsy samples from Helicobacter pylori-infected GML patients. In the mouse model, polarization of T helper 1 (tbet), T helper 2 (gata3), and regulatory T cell (foxp3) responses was evaluated by quantitative PCR. In humans, a significant increase in april gene expression was observed in GML compared to gastritis. APRIL-producing cells were eosinophilic polynuclear cells located within lymphoid infiltrates, and tumoral B lymphocytes were targeted by APRIL. Together, the results of this study demonstrate that the Treg-balanced inflammatory environment is important for gastric lymphomagenesis induced by Helicobacter species, and suggest the pro-tumorigenic potential of APRIL-producing eosinophils.
Collapse
|
|
37
|
Sheikh S, Lebel E, Trudel S. Belantamab mafodotin in the treatment of relapsed or refractory multiple myeloma. Future Oncol 2020; 16:2783-2798. [PMID: 32875817 DOI: 10.2217/fon-2020-0521] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Multiple myeloma remains an incurable disease, with a large proportion of patients in the relapsed/refractory setting often unable to achieve durable responses. Novel, well-tolerated and highly effective therapies in this patient population represent an unmet need. Preclinical studies have shown that B-cell maturation antigen is nearly exclusively expressed on normal and malignant plasma cells, thereby identifying it as a highly selective target for immunotherapeutic approaches. Belantamab mafodotin (GSK2857916, belamaf) is a first-in-class antibody-drug conjugate directed at B-cell maturation antigen and has shown promising activity in clinical trials. In this review, we provide an overview of belantamab mafodotin as a compound and present the available clinical efficacy and safety data in the treatment of relapsed/refractory multiple myeloma.
Collapse
Affiliation(s)
- Semira Sheikh
- Department of Medicine, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, M5G2C1, Canada
| | - Eyal Lebel
- Department of Medicine, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, M5G2C1, Canada
| | - Suzanne Trudel
- Department of Medicine, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, M5G2C1, Canada
| |
Collapse
|
|
38
|
Kampa M, Notas G, Stathopoulos EN, Tsapis A, Castanas E. The TNFSF Members APRIL and BAFF and Their Receptors TACI, BCMA, and BAFFR in Oncology, With a Special Focus in Breast Cancer. Front Oncol 2020; 10:827. [PMID: 32612943 PMCID: PMC7308424 DOI: 10.3389/fonc.2020.00827] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 04/28/2020] [Indexed: 12/11/2022] Open
Abstract
Tumor necrosis factor (TNF) superfamily consists of 19 ligands and 29 receptors and is related to multiple cellular events from proliferation and differentiation to apoptosis and tumor reduction. In this review, we overview the whole system, and we focus on A proliferation-inducing ligand (APRIL, TNFSF13) and B cell-activating factor (BAFF, TNFSF13B) and their receptors transmembrane activator and Ca2+ modulator (CAML) interactor (TACI, TNFRSF13B), B cell maturation antigen (BCMA, TNFRSF17), and BAFF receptor (BAFFR, TNFRSF13C). We explore their role in cancer and novel biological therapies introduced for multiple myeloma and further focus on breast cancer, in which the modulation of this system seems to be of potential interest, as a novel therapeutic target. Finally, we discuss some precautions which should be taken into consideration, while targeting the APRIL–BAFF system.
Collapse
Affiliation(s)
- Marilena Kampa
- Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, Heraklon, Greece
| | - George Notas
- Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, Heraklon, Greece
| | | | - Andreas Tsapis
- Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, Heraklon, Greece
| | - Elias Castanas
- Laboratory of Experimental Endocrinology, School of Medicine, University of Crete, Heraklon, Greece
| |
Collapse
|
|
39
|
Caraccio C, Krishna S, Phillips DJ, Schürch CM. Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions. Front Immunol 2020; 11:501. [PMID: 32391000 PMCID: PMC7193016 DOI: 10.3389/fimmu.2020.00501] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 03/04/2020] [Indexed: 12/15/2022] Open
Abstract
Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematological neoplasm in adults, comprising 1.8% of all cancers. With an annual incidence of ~30,770 cases in the United States, MM has a high mortality rate, leading to 12,770 deaths per year. MM is a genetically complex, highly heterogeneous malignancy, with significant inter- and intra-patient clonal variability. Recent years have witnessed dramatic improvements in the diagnostics, classification, and treatment of MM. However, patients with high-risk disease have not yet benefited from therapeutic advances. High-risk patients are often primary refractory to treatment or relapse early, ultimately resulting in progression toward aggressive end-stage MM, with associated extramedullary disease or plasma cell leukemia. Therefore, novel treatment modalities are needed to improve the outcomes of these patients. Bispecific antibodies (BsAbs) are immunotherapeutics that simultaneously target and thereby redirect effector immune cells to tumor cells. BsAbs have shown high efficacy in B cell malignancies, including refractory/relapsed acute lymphoblastic leukemia. Various BsAbs targeting MM-specific antigens such as B cell maturation antigen (BCMA), CD38, and CD138 are currently in pre-clinical and clinical development, with promising results. In this review, we outline these advances, focusing on BsAb drugs, their targets, and their potential to improve survival, especially for high-risk MM patients. In combination with current treatment strategies, BsAbs may pave the way toward a cure for MM.
Collapse
|
|
40
|
Xu S, Lam KP. Transmembrane Activator and CAML Interactor (TACI): Another Potential Target for Immunotherapy of Multiple Myeloma? Cancers (Basel) 2020; 12:cancers12041045. [PMID: 32340409 PMCID: PMC7226350 DOI: 10.3390/cancers12041045] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/17/2020] [Accepted: 04/21/2020] [Indexed: 02/06/2023] Open
Abstract
Multiple myeloma (MM) has emerged as the next most likely oncological or hematological disease indication amenable for cellular immunotherapy. Much of the attention has been focused on B cell maturation antigen (BCMA) as a unique cell surface protein on myeloma cells that is available for monoclonal antibodies, antibody drug conjugates (ADCs), T-cell redirecting bispecific molecules, and chimeric antigen receptor (CAR) T cell targeting. BCMA is a member of the tumor necrosis factor receptor (TNFR) superfamily that binds two ligands B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) and mediates the growth and survival of plasma and MM cells. Interestingly, transmembrane activator and CAML interactor (TACI), another TNFR superfamily member, also binds the same ligands and plays largely overlapping roles as BCMA in normal plasma and malignant MM cells. In this article, we review the biology of TACI, focusing on its role in normal B and plasma cells and malignant MM cells, and also discuss various ways to incorporate TACI as a potential target for immunotherapies against MM.
Collapse
Affiliation(s)
- Shengli Xu
- Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore
- Correspondence: (S.X); (K.-P.L)
| | - Kong-Peng Lam
- Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
- Correspondence: (S.X); (K.-P.L)
| |
Collapse
|
|
41
|
B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches. Leukemia 2020; 34:985-1005. [PMID: 32055000 PMCID: PMC7214244 DOI: 10.1038/s41375-020-0734-z] [Citation(s) in RCA: 292] [Impact Index Per Article: 58.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 01/29/2020] [Indexed: 12/17/2022]
Abstract
Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody–drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody–drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.
Collapse
|
|
42
|
Pont MJ, Hill T, Cole GO, Abbott JJ, Kelliher J, Salter AI, Hudecek M, Comstock ML, Rajan A, Patel BKR, Voutsinas JM, Wu Q, Liu L, Cowan AJ, Wood BL, Green DJ, Riddell SR. γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood 2019; 134:1585-1597. [PMID: 31558469 PMCID: PMC6871311 DOI: 10.1182/blood.2019000050] [Citation(s) in RCA: 241] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 08/20/2019] [Indexed: 12/15/2022] Open
Abstract
B-cell maturation antigen (BCMA) is a validated target for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM). Despite promising objective response rates, most patients relapse, and low levels of BCMA on a subset of tumor cells has been suggested as a probable escape mechanism. BCMA is actively cleaved from the tumor cell surface by the ubiquitous multisubunit γ-secretase (GS) complex, which reduces ligand density on tumor cells for CAR T-cell recognition and releases a soluble BCMA (sBCMA) fragment capable of inhibiting CAR T-cell function. Sufficient sBCMA can accumulate in the bone marrow of MM patients to inhibit CAR T-cell recognition of tumor cells, and potentially limit efficacy of BCMA-directed adoptive T-cell therapy. We investigated whether blocking BCMA cleavage by small-molecule GS inhibitors (GSIs) could augment BCMA-targeted CAR T-cell therapy. We found that exposure of myeloma cell lines and patient tumor samples to GSIs markedly increased surface BCMA levels in a dose-dependent fashion, concurrently decreased sBCMA concentrations, and improved tumor recognition by CAR T cells in vitro. GSI treatment of MM tumor-bearing NOD/SCID/γc-/- mice increased BCMA expression on tumor cells, decreased sBCMA in peripheral blood, and improved antitumor efficacy of BCMA-targeted CAR T-cell therapy. Importantly, short-term GSI administration to MM patients markedly increases the percentage of BCMA+ tumor cells, and the levels of BCMA surface expression in vivo. Based on these data, a US Food and Drug Administration (FDA)-approved clinical trial has been initiated, combining GSI with concurrent BCMA CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT03502577.
Collapse
Affiliation(s)
- Margot J Pont
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Tyler Hill
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Gabriel O Cole
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Joe J Abbott
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Jessica Kelliher
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Alexander I Salter
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA
- Department of Medicine, University of Washington, Seattle, WA
| | - Michael Hudecek
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany; and
| | - Melissa L Comstock
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Anusha Rajan
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA
| | | | - Jenna M Voutsinas
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Qian Wu
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Lingfeng Liu
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Andrew J Cowan
- Department of Medicine, University of Washington, Seattle, WA
| | - Brent L Wood
- Department of Medicine, University of Washington, Seattle, WA
| | - Damian J Green
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA
- Department of Medicine, University of Washington, Seattle, WA
| | - Stanley R Riddell
- Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA
- Department of Medicine, University of Washington, Seattle, WA
| |
Collapse
|
|
43
|
Sanchez E, Smith EJ, Yashar MA, Patil S, Li M, Porter AL, Tanenbaum EJ, Schlossberg RE, Soof CM, Hekmati T, Tang G, Wang CS, Chen H, Berenson JR. The Role of B-Cell Maturation Antigen in the Biology and Management of, and as a Potential Therapeutic Target in, Multiple Myeloma. Target Oncol 2019; 13:39-47. [PMID: 29230672 DOI: 10.1007/s11523-017-0538-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
B-cell maturation antigen (BCMA) was originally identified as a cell membrane receptor, expressed exclusively on late stage B-cells and plasma cells (PCs). Investigations of BCMA as a target for therapeutic intervention in multiple myeloma (MM) were initiated in 2007, using cSG1 as a naked antibody (Ab) as well as an Ab-drug conjugate (ADC) targeting BCMA, ultimately leading to ongoing clinical studies for previously treated MM patients. Since then, multiple companies have developed anti-BCMA-directed ADCs. Additionally, there are now three bispecific antibodies in development, which bind to both BCMA and CD3ε on T-cells. This latter binding results in T-cell recruitment and activation, causing target cell lysis. More recently, T-cells have been genetically engineered to recognize BCMA-expressing cells and, in 2013, the first report of anti-BCMA-chimeric antigen receptor T-cells showed that these killed MM cell lines and human MM xenografts in mice. BCMA is also solubilized in the blood (soluble BCMA [sBCMA]) and MM patients with progressive disease have significantly higher sBCMA levels than those responding to treatment. sBCMA circulating in the blood may limit the efficacy of these anti-BCMA-directed therapies. When sBCMA binds to B-cell activating factor (BAFF), BAFF is unable to perform its major biological function of inducing B-cell proliferation and differentiation into Ab-secreting PC. However, the use of γ-secretase inhibitors, which prevent shedding of BCMA from PCs, may improve the efficacy of these BCMA-directed therapies.
Collapse
Affiliation(s)
- Eric Sanchez
- Institute for Myeloma & Bone Cancer Research, 9201 W Sunset Blvd, Suite 300, West Hollywood, CA, 90069, USA
| | - Emily J Smith
- Institute for Myeloma & Bone Cancer Research, 9201 W Sunset Blvd, Suite 300, West Hollywood, CA, 90069, USA
| | - Moryel A Yashar
- Institute for Myeloma & Bone Cancer Research, 9201 W Sunset Blvd, Suite 300, West Hollywood, CA, 90069, USA
| | - Saurabh Patil
- Institute for Myeloma & Bone Cancer Research, 9201 W Sunset Blvd, Suite 300, West Hollywood, CA, 90069, USA
| | - Mingjie Li
- Institute for Myeloma & Bone Cancer Research, 9201 W Sunset Blvd, Suite 300, West Hollywood, CA, 90069, USA
| | - Autumn L Porter
- Institute for Myeloma & Bone Cancer Research, 9201 W Sunset Blvd, Suite 300, West Hollywood, CA, 90069, USA
| | - Edward J Tanenbaum
- Institute for Myeloma & Bone Cancer Research, 9201 W Sunset Blvd, Suite 300, West Hollywood, CA, 90069, USA
| | - Remy E Schlossberg
- Institute for Myeloma & Bone Cancer Research, 9201 W Sunset Blvd, Suite 300, West Hollywood, CA, 90069, USA
| | - Camilia M Soof
- Institute for Myeloma & Bone Cancer Research, 9201 W Sunset Blvd, Suite 300, West Hollywood, CA, 90069, USA
| | - Tara Hekmati
- Institute for Myeloma & Bone Cancer Research, 9201 W Sunset Blvd, Suite 300, West Hollywood, CA, 90069, USA
| | - George Tang
- Institute for Myeloma & Bone Cancer Research, 9201 W Sunset Blvd, Suite 300, West Hollywood, CA, 90069, USA
| | - Cathy S Wang
- Institute for Myeloma & Bone Cancer Research, 9201 W Sunset Blvd, Suite 300, West Hollywood, CA, 90069, USA
| | - Haiming Chen
- Institute for Myeloma & Bone Cancer Research, 9201 W Sunset Blvd, Suite 300, West Hollywood, CA, 90069, USA
| | - James R Berenson
- Institute for Myeloma & Bone Cancer Research, 9201 W Sunset Blvd, Suite 300, West Hollywood, CA, 90069, USA.
| |
Collapse
|
|
44
|
Fehres CM, van Uden NO, Yeremenko NG, Fernandez L, Franco Salinas G, van Duivenvoorde LM, Huard B, Morel J, Spits H, Hahne M, Baeten DLP. APRIL Induces a Novel Subset of IgA + Regulatory B Cells That Suppress Inflammation via Expression of IL-10 and PD-L1. Front Immunol 2019; 10:1368. [PMID: 31258536 PMCID: PMC6587076 DOI: 10.3389/fimmu.2019.01368] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 05/29/2019] [Indexed: 12/26/2022] Open
Abstract
Regulatory B cells (Bregs) are immunosuppressive cells that modulate immune responses through multiple mechanisms. The signals required for the differentiation and activation of these cells remain still poorly understood. We have already shown that overexpression of A PRoliferation-Inducing Ligand (APRIL) reduces the incidence and severity of collagen-induced arthritis (CIA) in mice. Furthermore, we have described that APRIL, but not BAFF, promoted IL-10 production and regulatory functions in human B cells. Therefore, we hypothesized that APRIL, but not BAFF, may be involved in the induction and/or activation of IL-10 producing Bregs that suppress inflammatory responses in vitro and in vivo. Here, we describe that APRIL promotes the differentiation of naïve human B cells to IL-10-producing IgA+ B cells. These APRIL-induced IgA+ B cells display a Breg phenotype and inhibit T cell and macrophage responses through IL-10 and PD-L1. Moreover, APRIL-induced IL-10 producing Bregs suppress inflammation in vivo in experimental autoimmune encephalitis (EAE) and contact hypersensitivity (CHS) models. Finally, we showed a strong correlation between APRIL and IL-10 in the inflamed synovial tissue of inflammatory arthritis patients. Collectively, these observations indicate the potential relevance of this novel APRIL-induced IgA+ Breg population for immune homeostasis and immunopathology.
Collapse
Affiliation(s)
- Cynthia M Fehres
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Centre, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.,Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Nathalie O van Uden
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Centre, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.,Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Nataliya G Yeremenko
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Centre, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.,Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Leticia Fernandez
- Centre National de la Recherche Scientifique, Universite de Montpellier, Montpellier, France
| | - Gabriela Franco Salinas
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Centre, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Leonie M van Duivenvoorde
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Centre, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.,Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Bertrand Huard
- Institute for Advanced Biosciences, INSERM U1209, University Grenoble Alpes, Grenoble, France
| | - Jacques Morel
- Department of Rheumatology, CHU de Montpellier, Montpellier University, Montpellier, France
| | - Hergen Spits
- Amsterdam UMC, University of Amsterdam, and AIMM Therapeutics, Amsterdam, Netherlands
| | - Michael Hahne
- Centre National de la Recherche Scientifique, Universite de Montpellier, Montpellier, France
| | - Dominique L P Baeten
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Centre, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.,Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| |
Collapse
|
|
45
|
Friedman KM, Garrett TE, Evans JW, Horton HM, Latimer HJ, Seidel SL, Horvath CJ, Morgan RA. Effective Targeting of Multiple B-Cell Maturation Antigen-Expressing Hematological Malignances by Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor T Cells. Hum Gene Ther 2019; 29:585-601. [PMID: 29641319 DOI: 10.1089/hum.2018.001] [Citation(s) in RCA: 162] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
B-cell maturation antigen (BCMA) expression has been proposed as a marker for the identification of malignant plasma cells in patients with multiple myeloma (MM). Nearly all MM tumor cells express BCMA, while normal tissue expression is restricted to plasma cells and a subset of mature B cells. Consistent BCMA expression was confirmed on MM biopsies (29/29 BCMA+), and it was further demonstrated that BCMA is expressed in a substantial number of lymphoma samples, as well as primary chronic lymphocytic leukemia B cells. To target BCMA using redirected autologous T cells, lentiviral vectors (LVV) encoding chimeric antigen receptors (CARs) were constructed with four unique anti-BCMA single-chain variable fragments, fused to the CD137 (4-1BB) co-stimulatory and CD3ζ signaling domains. One LVV, BB2121, was studied in detail, and BB2121 CAR-transduced T cells (bb2121) exhibited a high frequency of CAR + T cells and robust in vitro activity against MM cell lines, lymphoma cell lines, and primary chronic lymphocytic leukemia peripheral blood. Based on receptor quantification, bb2121 recognized tumor cells expressing as little as 222 BCMA molecules per cell. The in vivo pharmacology of anti-BCMA CAR T cells was studied in NSG mouse models of human MM, Burkitt lymphoma, and mantle cell lymphoma, where mice received a single intravenous administration of vehicle, control vector-transduced T cells, or anti-BCMA CAR-transduced T cells. In all models, the vehicle and control CAR T cells failed to inhibit tumor growth. In contrast, treatment with bb2121 resulted in rapid and sustained elimination of the tumors and 100% survival in all treatment models. Together, these data support the further development of anti-BCMA CAR T cells as a potential treatment for not only MM but also some lymphomas.
Collapse
|
|
46
|
Eckhert E, Hewitt R, Liedtke M. B-cell maturation antigen directed monoclonal antibody therapies for multiple myeloma. Immunotherapy 2019; 11:801-811. [PMID: 31094254 DOI: 10.2217/imt-2018-0199] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Multiple myeloma affects 30,000 new patients in the USA yearly, with 5-year median overall survival rates of 82, 62 and 40% for patients in groups I, II and III of the revised international staging system. Novel therapeutic and prognostic tools are changing the way we treat patients with this historically difficult to manage condition. B-cell maturation antigen (BCMA) represents an ideal therapeutic target in myeloma because of its high expression rate and high specificity for myeloma cells. Preclinical data indicate that anti-BCMA monoclonal antibody therapies are highly potent, and initial data from Phase I clinical trials indicate that these drugs are well tolerated. Numerous ongoing Phase I and II clinical trials of anti-BCMA monoclonal antibodies are currently under way.
Collapse
Affiliation(s)
- Erik Eckhert
- Department of Medicine, Stanford University Hospital, 300 Pasteur Drive, Stanford, CA 94305, USA
| | - Rhonda Hewitt
- Department of Medicine, Division of Hematology/Oncology, Stanford University Hospital, 875 Blake Wilbur Drive, Stanford, CA 94305, USA
| | - Michaela Liedtke
- Department of Medicine, Division of Hematology/Oncology, Stanford University Hospital, 875 Blake Wilbur Drive, Stanford, CA 94305, USA
| |
Collapse
|
|
47
|
Fouladseresht H, Ziaee SM, Erfani N, Doroudchi M. Serum Levels of APRIL Increase in Patients with Glioma, Meningioma and Schwannoma. Asian Pac J Cancer Prev 2019; 20:751-756. [PMID: 30909681 PMCID: PMC6825795 DOI: 10.31557/apjcp.2019.20.3.751] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Objective: Brain tumors are of high mortality and morbidity for which there is still no cure. The TNF family cytokine, A Proliferation Inducing Ligand (APRIL), is shown to help proliferation and development of tumor cells. We assessed serum levels of APRIL in patients with glioma, meningioma and schwannoma in comparison to healthy individuals. Methods: Peripheral blood samples of 68 patients with brain tumors, divided into three groups of gliomas (n=25), meningiomas (n=30) and schwannomas (n=13), as well as 45 healthy individuals were obtained. Serum samples were prepared and stored in -40°C until usage. Using a commercial ELISA method, APRIL concentration was measured in each serum sample. The obtained data were then analyzed using SPSS software. Results: APRIL serum levels were higher in all patients compared to the controls (P<0.001). Moreover, APRIL serum levels were higher in each of the tumor bearing groups (gliomas, meningiomas and schwannomas) in comparison to the controls (P<0.001, <0.001 and =0.001, respectively). Comparing APRIL between the patients groups showed no significant difference. Age and gender showed no significant correlation with serum APRIL levels, although the age of patients in glioma group was significantly lower than controls (P=0.017). The serum APRIL levels in gliomas with histological grade showed no difference, but in meningiomas, it was lower in tumors with higher grades (P= 0.011). Conclusion: Increased serum levels of APRIL in patients with meningioma and schwannoma as well as glioma may indicate a common role of this cytokine in brain tumors.
Collapse
Affiliation(s)
- Hamed Fouladseresht
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Seyyed Mohyeddin Ziaee
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Nasrollah Erfani
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. ,Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehrnoosh Doroudchi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. ,Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| |
Collapse
|
|
48
|
Gavriatopoulou M, Ntanasis-Stathopoulos I, Dimopoulos MA, Terpos E. Anti-BCMA antibodies in the future management of multiple myeloma. Expert Rev Anticancer Ther 2019; 19:319-326. [PMID: 30810049 DOI: 10.1080/14737140.2019.1586539] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
INTRODUCTION B-cell maturation antigen (BCMA) belongs to the tumor necrosis factor receptor family and is expressed on late B-cells and plasma cells. Serum BCMA is elevated in patients with multiple myeloma (MM) and chronic lymphocytic leukemia (CLL), and might represent a novel prognostic and monitoring tool. Serum BCMA levels can predict both progression free survival (PFS) and overall survival (OS). Several therapeutic strategies are currently under investigation including BCMA-directed monoclonal Abs (either naked or with drug conjugates, and bispecific Abs) and cellular T-cell therapies (chimeric antigen receptor T-cells) with impressive clinical results. Areas covered: This review aims to present the mechanisms of action and the available data on efficacy and safety of therapies targeting BCMA. Expert opinion: The preliminary preclinical and clinical results from the phase 1 and 2 studies have demonstrated significant activity of the anti-BCMA therapeutic strategies. The main toxicities induced include Cytokine Release Syndrome (CRS) and ocular toxicity. The management of these adverse events remains currently an issue of controversy.
Collapse
Affiliation(s)
- Maria Gavriatopoulou
- a Oncology Department, Department of Therapeutics, Alexandra Hospital , National and Kapodistrian University of Athens , Athens , Greece
| | - Ioannis Ntanasis-Stathopoulos
- a Oncology Department, Department of Therapeutics, Alexandra Hospital , National and Kapodistrian University of Athens , Athens , Greece
| | - Meletios Athanasios Dimopoulos
- a Oncology Department, Department of Therapeutics, Alexandra Hospital , National and Kapodistrian University of Athens , Athens , Greece
| | - Evangelos Terpos
- a Oncology Department, Department of Therapeutics, Alexandra Hospital , National and Kapodistrian University of Athens , Athens , Greece
| |
Collapse
|
|
49
|
The role of APRIL - A proliferation inducing ligand - In autoimmune diseases and expectations from its targeting. J Autoimmun 2018; 95:179-190. [DOI: 10.1016/j.jaut.2018.10.016] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 10/17/2018] [Indexed: 12/12/2022]
|
|
50
|
Sanchez E, Tanenbaum EJ, Patil S, Li M, Soof CM, Vidisheva A, Waterman GN, Hekmati T, Tang G, Wang CS, Chen H, Berenson J. The clinical significance of B-cell maturation antigen as a therapeutic target and biomarker. Expert Rev Mol Diagn 2018; 18:319-329. [PMID: 29504446 DOI: 10.1080/14737159.2018.1448269] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Affiliation(s)
- Eric Sanchez
- Institute for Myeloma and Bone Cancer Research (IMBCR), West Hollywood, CA, USA
| | - Edward J. Tanenbaum
- Institute for Myeloma and Bone Cancer Research (IMBCR), West Hollywood, CA, USA
| | - Saurabh Patil
- Institute for Myeloma and Bone Cancer Research (IMBCR), West Hollywood, CA, USA
| | - Mingjie Li
- Institute for Myeloma and Bone Cancer Research (IMBCR), West Hollywood, CA, USA
| | - Camilia M. Soof
- Institute for Myeloma and Bone Cancer Research (IMBCR), West Hollywood, CA, USA
| | | | - Gabriel N. Waterman
- Keck School of Medicine, University of Southern California - Los Angeles, Los Angeles, CA, USA
| | - Tara Hekmati
- Institute for Myeloma and Bone Cancer Research (IMBCR), West Hollywood, CA, USA
| | - George Tang
- Institute for Myeloma and Bone Cancer Research (IMBCR), West Hollywood, CA, USA
| | - Cathy S. Wang
- Institute for Myeloma and Bone Cancer Research (IMBCR), West Hollywood, CA, USA
| | - Haiming Chen
- Institute for Myeloma and Bone Cancer Research (IMBCR), West Hollywood, CA, USA
| | - James Berenson
- Institute for Myeloma and Bone Cancer Research (IMBCR), West Hollywood, CA, USA
| |
Collapse
|